Prediction of damage trajectories in systemic sclerosis using group-based trajectory modelling.

OBJECTIVES: Damage accrual in SSc can be tracked using the Scleroderma Clinical Trials Consortium Damage Index (DI). Our goal was to develop a prediction model for damage accrual in SSc patients with early disease. METHODS: Using patients with <2 years disease duration from Canada and Australia as a derivation cohort, and from the Netherlands as a validation cohort, we used group-based trajectory modelling (GBTM) to determine 'good' and 'bad' latent damage trajectories. We developed a prediction model from this analysis and applied it to patients from derivation and validation cohorts. We plotted the actual DI trajectories of the patients predicted to be in 'good' or 'bad' groups. RESULTS: We found that the actual trajectories of damage accumulation for lcSSc and dcSSc were very different, so we studied each subset separately. GBTM found two distinct trajectories in lcSSc and three in dcSSc. We collapsed the two worse trajectories in the dcSSc into one group and developed a prediction model for inclusion in either 'good' or 'bad' trajectories. The performance of models using only baseline DI and sex was excellent with ROC AUC of 0.9313 for lcSSc and 0.9027 for dcSSc. Using this model, we determined whether patients would fall into 'good' or 'bad' trajectory groups and then plotted their actual trajectories which showed clear differences between the predicted 'good' and 'bad' cases in both derivation and validation cohorts. CONCLUSIONS: A simple model using only cutaneous subset, baseline DI and sex can predict damage accumulation in early SSc.

Development and validation of a patient-reported outcome instrument for skin involvement in patients with systemic sclerosis.

OBJECTIVES: We developed a patient-reported outcome (PRO) instrument to assess the skin-related quality of life in patients with systemic sclerosis (SSc). METHODS: Participants with SSc provided input on skin-related health effects through focus groups. We developed items for scleroderma skin PRO (SSPRO) to encompass these effects. Further consideration from cognitive interviews and an expert panel led to reduction and modification of items. A 22-item SSPRO was field tested. Psychometric analysis included test-retest reliability, internal consistency and exploratory factor analysis (EFA). Construct validity was assessed through correlation with other participant and physician-assessed measures. RESULTS: 140 participants completed the SSPRO: mean age was 53.4 years, median disease duration was 5 years, 82.1% were female and 32.9% had diffuse cutaneous SSc. EFA supported four factors in SSPRO corresponding to hypothesised constructs: physical effects, physical limitations, emotional effects and social effects. Removal of 4/22 items resulted in acceptable goodness-of-fit statistics. Test-retest reliability (intraclass correlation coefficient=0.61-0.83) was moderate to high and internal consistency (Cronbach's α=0.89-0.96) was high. SSPRO correlated strongly with other participant-reported measures (r=0.59-0.88) suggesting construct validity, and less well with physician-assessed measures (r=0.31-0.40). SSPRO scores were significantly different for each level of participant-reported skin severity, and for limited versus diffuse cutaneous SSc. CONCLUSIONS: SSPRO has been developed with extensive patient input and demonstrates evidence for reliability and validity. It is complementary to existing measures of SSc skin involvement with emphasis on the patient's experience. Further research is needed to assess its sensitivity to change.

Independent impact of gout on the risk of diabetes mellitus among women and men: a population-based, BMI-matched cohort study.

OBJECTIVE: Evidence on the potential independent impact of gout on the risk of diabetes is limited to a single study of men with a high cardiovascular risk profile. Our objective was to examine this relation in the general population, particularly among women. METHODS: We conducted a sex-stratified matched cohort study using data from The Health Improvement Network (THIN), an electronic medical records database representative of the UK general population. Up to five non-gout individuals were matched to each case of incident gout by year of birth, year of enrolment and body mass index (BMI). Multivariate HRs for incident diabetes were calculated after additionally adjusting for smoking, alcohol consumption, physician visits, comorbidities and medication use. RESULTS: Among 35 339 gout patients (72.4% men, mean age of 62.7 years), the incidence rates of diabetes in women and men were 10.1 and 9.5 cases per 1000 person-years, respectively, whereas the corresponding rates were 5.6 and 7.2 cases per 1000 person-years among 137 056 non-gout subjects. The BMI-matched univariate and multivariate HRs of diabetes were higher among women compared with those among men (1.71; 95% CI 1.51 to 1.93 vs 1.22; 95% CI 1.13 to 1.31) and (1.48; 95% CI 1.29 to 1.68 vs 1.15; 95% CI 1.06 to 1.24), respectively (p values for interaction <0.001). This sex difference persisted across age-specific subgroups. CONCLUSIONS: This general population-based study suggests that gout may be independently associated with an increased risk of diabetes and that the magnitude of association is significantly larger in women than in men.

The relationship between skin symptoms and the scleroderma modification of the health assessment questionnaire, the modified Rodnan skin score, and skin pathology in patients with systemic sclerosis.

OBJECTIVE: To determine how well skin symptoms considered specific to SSc are captured by patient reported outcomes currently used for assessing patients with SSc, the SHAQ, or skin disease, the Skindex-29; and how well these symptoms correlate with the extent of skin disease on physical exam and skin pathology. METHODS: SSc patients completed the scleroderma modification of the Health Assessment Questionnaire (SHAQ), Skindex-29 and a Skin Symptom Assessment questionnaire developed for this study. Correlations were assessed between the Skin Symptom Assessment and SHAQ, Skindex-29, modified Rodnan skin score, and skin pathological features including myofibroblast staining completed on the same date. RESULTS: Tight, hard and rigid/stiff skin symptoms correlated moderately highly with the modified Rodnan skin score (r = 0.445, P = 0.0008; r = 0.486, P = 0.0002; and r = 0.488, P = 0.0002, respectively). Tight skin symptoms correlated moderately with myofibroblast infiltration (r = 0.544, P = 0.0023) and hyalinized collagen (r = 0.442, P = 0.0164), while both hard and rigid/stiff skin correlated moderately with inflammation (r = 0.401, P = 0.0310 and r = 0.513, P = 0.0045), myofibroblast infiltration(r = 0.480, P = 0.0084 and r = 0.527, P = 0.0033) and hyalinized collagen (r = 0.453, P = 0.0137 and r = 0.478, P = 0.0087), while the SHAQ was not found to correlate with any of these pathological changes. In contrast, painful skin symptoms correlated moderately with the SHAQ (r = 0.413, P = 0.0073), and with the three domains of Skindex-29: Symptoms, Emotions and Functioning. Skindex-29 indicates that dcSSc patient skin symptoms are nearly as severe as those of patients with psoriasis or atopic dermatitis. CONCLUSION: Patient reported skin symptoms correlate with clinical and pathological measures in the skin. A validated patient reported skin symptom instrument might considerably improve evaluation of SSc skin disease.

Changes in forced vital capacity over time in systemic sclerosis: application of group-based trajectory modelling.

OBJECTIVE: An accelerated rate of decline in forced vital capacity (FVC) affects >50% of patients with SSc but data on the variability and determinants of this change are scarce. We sought to identify trajectories of FVC and their associated variables in SSc patients over a 12-year period. METHODS: Clinical and pulmonary function data were retrospectively collected. SSc patients with three or more FVC values were included. Group-based modelling was used to cluster similar FVC patterns into trajectories. Baseline variables were associated with the trajectories using multinomial logistic regression. The effect of CYC on FVC was examined with each trajectory as a time-varying covariate. RESULTS: In 254 SSc patients we identified seven distinct FVC trajectories: very low slow decline (5.5%), very low improve (13.8%), low fast decline (9.5%), low stable (19.7%), low-normal improve (31.1%), normal improve (16.1%) and normal stable (4.3%). Younger age and the presence of pulmonary hypertension, Interstitial lung disease and shortness of breath at baseline significantly increased the odds of declining trajectories vs the reference trajectory (low-normal improve). CYC was associated with FVC improvement in the low fast decline trajectory. CONCLUSION: The course of FVC in SSc was highly variable, with improvement and stability experienced even by those with low baseline FVC. Trajectory modelling was able to identify SSc patients who were most likely to experience FVC decline and thus could be a useful tool for patient management as well as clinical trial design.

Diabetes incidence in psoriatic arthritis, psoriasis and rheumatoid arthritis: a UK population-based cohort study.

OBJECTIVE: The objective of this study was to evaluate the incidence of diabetes among patients with PsA and RA in the general population. METHODS: We conducted a cohort study using an electronic medical records database representative of the UK general population (1986-2010). We estimated hazard ratios (HRs) for incident diabetes in PsA, psoriasis and RA cohorts compared with age- and sex-matched comparison cohorts without the corresponding conditions, adjusting for BMI, smoking, alcohol use, co-morbidities and glucocorticoids at baseline. RESULTS: Cohorts included 4196 persons with PsA, 59 281 with psoriasis and 11 158 with RA, with mean follow-up times of 5.9, 5.8 and 5.5 years, respectively. Incidence rates for diabetes were 7.3, 6.4 and 6.3 cases per 1000 person-years among individuals with PsA, psoriasis and RA, respectively. Age- and sex-matched HRs for diabetes were 1.72 (95% CI 1.46, 2.02) in PsA, 1.39 (95% CI 1.32, 1.45) in psoriasis and 1.12 (95% CI 1.01, 1.25) in RA. After adjustment for BMI, smoking and alcohol, the HRs were attenuated substantially (1.43, 1.24 and 1.00, respectively). With further adjustment for baseline glucocorticoid use and co-morbidities, the HRs were 1.33 (1.09, 1.61) in PsA, 1.21 (1.15, 1.27) in psoriasis and 0.94 (0.84, 1.06) in RA. CONCLUSION: This general population study suggests an increased incidence of diabetes in PsA and RA, which is substantially explained by obesity and lifestyle factors. These findings support the importance of managing such factors in PsA and RA patients.

The risk of cardiovascular disease in systemic sclerosis: a population-based cohort study.

OBJECTIVES: To evaluate the risk of incident myocardial infarction (MI), stroke and peripheral vascular disease (PVD) in individuals with systemic sclerosis (SSc) in a general population context. METHODS: We conducted a cohort study using a UK primary care database containing records from 1986 to 2011. SSc diagnoses, outcomes and cardiovascular risk factors were identified from electronic medical records. We conducted two cohort analyses: (1) MI and stroke, and (2) PVD, excluding individuals with prevalent disease at baseline for each analysis. We estimated HRs comparing SSc with age-, sex- and entry time-matched comparison cohorts, adjusting for potential cardiovascular risk factors. RESULTS: Among 865 individuals with SSc (85.8% women, mean age 58.7 years), the incidence rates (IRs) of MI and stroke were 4.4 and 4.8 per 1000 person-years (PY), versus 2.5 and 2.5 per 1000 PY in the comparison cohort. The corresponding adjusted HRs were 1.80 (95% CI 1.07 to 3.05) for MI and 2.61 (95% CI 1.54 to 4.44) for stroke. Among 858 individuals with SSc (85.3% female, mean age 58.9 years), the IR of PVD was 7.6 per 1000 PY versus 1.9 per 1000 PY in the comparison cohort, with an adjusted HR of 4.35 (95% CI 2.74 to 6.93). CONCLUSIONS: These findings provide the first general population-based evidence that SSc is associated with an increased risk of developing MI, stroke and PVD. Further insight into disease mechanisms, as well as how disease subtype, organ involvement and medication use may alter these increased risks, is needed.

Damage Trajectories in Systemic Sclerosis Using Group-Based Trajectory Modeling.

OBJECTIVE: Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive organ damage, which can be measured using the Scleroderma Clinical Trials Consortium Damage Index (SCTC-DI). We aimed to identify whether distinct trajectories of damage accrual exist and to determine which variables are associated with different trajectory groups. METHODS: Incident cases of SSc (<2 years) were identified in the Australian Scleroderma Interest Group and Canadian Scleroderma Research Group prospective registries. Group-based trajectory modeling was used to identify SCTC-DI trajectories over the cohort's first 5 annual visits. Baseline variables associated with trajectory membership in a univariate analysis were examined in multivariable models. RESULTS: A total of 410 patients were included. Three trajectory groups were identified: low (54.6%), medium (36.2%), and high (10.3%) damage. Patients with faster damage accrual had higher baseline SCTC-DI scores. Older age (odds ratio [OR] 1.57 [95% confidence interval (95% CI) 1.18-2.10]), male sex (OR 2.55 [95% CI 1.10-5.88]), diffuse disease (OR 6.7 [95% CI 2.57-17.48]), tendon friction rubs (OR 5.4 [95% CI 1.86-15.66]), and elevated C-reactive protein level (OR 1.98 [95% CI 1.49-2.63]) increased the odds of being in the high-damage group versus the reference (low damage), whereas White ethnicity (OR 0.31 [95% CI 0.12-0.75]) and anticentromere antibodies (OR 0.24 [95% CI 0.07-0.77]) decreased the odds. CONCLUSION: We identified 3 trajectories of damage accrual in a combined incident SSc cohort. Several characteristics increased the odds of belonging to worse trajectories. These findings may be helpful in recognizing patients in whom early aggressive treatment is necessary.

Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement.

Importance: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management. Objective: To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2. Evidence Review: The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence. Findings: The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined. Conclusions and Relevance: DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2.

Early Cardiovascular Disease After the Diagnosis of Systemic Sclerosis.

PURPOSE: The purpose of this study is to assess risk and time trends of newly recorded myocardial infarction and stroke in cases with systemic sclerosis. METHODS: We conducted a matched incident cohort study (1996-2010) among patients satisfying at least one of the following: 1) diagnosis of systemic sclerosis on at least 2 visits within a 2-year period by a nonrheumatologist physician; or 2) diagnosis of systemic sclerosis on at least one visit by a rheumatologist or from hospitalization; as well as receiving no prior systemic sclerosis diagnosis between 1990 and 1995. Ten controls were matched by birth year, sex, and calendar year of exposure from the general population for each case. Incident myocardial infarction, stroke, and myocardial infarction or stroke was recorded from hospital or death certificates. We estimated incidence rate ratios and hazard ratios (HRs) after adjusting for confounders. RESULTS: Among 1239 individuals with systemic sclerosis and no history of myocardial infarction (83% female, 56 years old), the incidence rate for myocardial infarction was 13.0/1000 person-years vs 4.1/1000 person-years in the comparison cohort. The incidence rate for stroke was 8.0/1000 person-years vs 3.7/1000 among controls. The adjusted HRs were 3.49 (95% confidence interval [CI], 2.52-4.83) and 2.35 (95% CI, 1.59-3.48) for myocardial infarction and stroke, respectively. For myocardial infarction and stroke, the risk was highest within the first year following diagnosis (HR 8.95; 95% CI, 5.43-14.74 and HR 5.25; 95% CI, 2.90-9.53, respectively). CONCLUSION: This large general population-based study indicates an increased risk of myocardial infarction and stroke in patients with systemic sclerosis, especially within the first year of diagnosis.

An evaluation of autoimmune antibody testing patterns in a Canadian health region and an evaluation of a laboratory algorithm aimed at reducing unnecessary testing.

Autoantibody tests are often ordered inappropriately. We aimed to evaluate the ordering patterns of these tests in our local health region and to develop a laboratory algorithm aimed at reducing unnecessary tests. Laboratory data including the number and sequence of tests, ordering physician specialties and results for antinuclear (ANA), extractable nuclear antigen (ENA) and anti-double stranded DNA (anti-dsDNA) antibody tests from 2007 to 2009 were evaluated. Based on this information and a clinical consensus meeting, an algorithm was developed and applied retrospectively to 1 year of inpatient laboratory data to simulate potential cost savings. We identified a large volume of these autoantibody tests performed, equating to testing costs of $862,706.72, where less than 17 % of each were positive. Repeated ANA tests were mostly ordered after a previously negative result, and 1 % of patients with negative results changed to ≥1:160 on repeat testing. Close to half of all ENA and anti-dsDNA tests that were ordered were done so simultaneously with ANA, suggesting their use as screening tests. This was done more frequently in the inpatient setting. An algorithm was developed where ENA and anti-dsDNA tests would be cancelled if ANA was negative in the same sample. ANA repeated within 1 year would be cancelled and the prior result provided. Application of the algorithm retrospectively simulated a 30 % cost savings. Repeat testing and simultaneous ordering of multiple tests contributed to the excessive ordering of autoantibody tests in our health region. Our proposed algorithm would reduce testing costs and should be accompanied by appropriate educational information for physicians.

Minimizing treatment without compromising cure with primary surveillance for clinical stage I embryonal predominant nonseminomatous testicular cancer: a population based analysis from British Columbia.

PURPOSE: We evaluated the outcome of patients with embryonal carcinoma predominant (ECP) clinical stage (CS) I nonseminomatous testicular germ cell tumors (NSGCT) treated with primary surveillance or primary retroperitoneal lymph node dissection (RPLND). MATERIALS AND METHODS: This study was a retrospective evaluation of the pathology, use of chemotherapy, surgery and outcomes in all patients with CS I NSGCT who were diagnosed within the province of British Columbia between 1990 and 2000. RESULTS: A total of 205 patients were identified, of whom 107 (52%) had ECP disease. Of these patients 72 (67%) underwent primary surveillance, 32 (33%) underwent primary RPLND and 3 refused treatment. Median followup was 4 years (range 1 to 10). In the primary surveillance group 24 patients (33%) had relapse and all were treated initially with chemotherapy with 6 also requiring RPLND. The remaining 48 patients (67%) in the surveillance group were cured of disease with orchiectomy alone. In the primary RPLND group 18 patients (56%) had pathological stage I disease and 14 (44%) had pathological stage II disease. In the primary RPLND group 15 patients (46%) required chemotherapy with 11 (34%) receiving adjuvant chemotherapy and 4 receiving chemotherapy for post-RPLND relapse. No deaths from ECP testicular cancer occurred in either group. The 4-year chemotherapy-free survival rate was 65% in the surveillance group vs 50% in the RPLND group (p = 0.2). CONCLUSIONS: For appropriately selected patients with CS I ECP NSGCT, primary surveillance results in fewer therapeutic interventions compared to RPLND without compromising the probability of cure.

Asian race and impact on outcomes after radical radiotherapy for localized prostate cancer.

PURPOSE: We compared survival outcomes in patients of Asian descent treated with curative intent radiation therapy for prostate cancer with that in the nonAsian population in British Columbia, Canada. MATERIALS AND METHODS: Since 1994, 1,872 men treated with curative intent radiotherapy for prostate cancer have been followed prospectively at our provincial institution, where cancer care delivery is coordinated for the province of British Columbia. Patients are treated uniformly based on provincial policies and guidelines. Patients were divided into 63 Asian (3.6%) and 1,804 nonAsian (96.4%) patients by surname with Asian names checked by telephone contact. Three risk groups were defined based on pretreatment prostate specific antigen, biopsy Gleason score and clinical T staging. For the whole cohort and each risk group survival was estimated using the Kaplan-Meier method and comparisons were made between the Asian and nonAsian populations. RESULTS: The mean age of Asian and nonAsian men was 71.5 and 71 years, respectively. Median prostate specific antigen was 11.4 and 10 ng/ml, respectively (p = 0.7). Median Gleason score was 7 for Asian patients and 6 for nonAsian patients (p = 0.002). There were twice the percentage of Asian patients with Gleason scores 8 or greater than nonAsian (26.5% vs 13.8%, p = 0.003). More Asian patients had stage 3 or 4 disease than nonAsian (44.8% vs 34.9%, p = 0.095). A greater proportion of Asian patients were classified as being at high risk than the nonAsian population (60.3% vs 47.6%, p = 0.04). For the entire cohort, and the low, intermediate and high risk groups there were no differences in time to first failure, or cause specific or overall survival for Asian vs nonAsian men. CONCLUSIONS: A greater proportion of patients of Asian descent present with high risk prostate cancer than nonAsian patients, which could be due to intrinsic biological differences and/or differences in diagnostic patterns. Survival outcomes after radiotherapy are the same for the 2 populations.