Aladdin J. Mohammad

Incidence and survival rates in Wegener's granulomatosis, microscopic polyangiitis, Churg–Strauss syndrome and polyarteritis nodosa

OBJECTIVE To estimate the incidence of and survival rates for WG, microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS) and PAN within a defined population in southern Sweden. METHODS Cases were retrieved using hospital records and a serology database. All new cases of WG, MPA, CSS and PAN between 1997 and 2006 were included, provided they met pre-defined criteria, and were followed until 30 June 2008. The study area comprised two health care districts with a total population of 641 000. The standardized mortality ratio (SMR) was estimated using Swedish population data as a reference. RESULTS A total of 140 (WG, 63; MPA 65; CSS 6; and PAN 6) cases (52% women) with a median age of 67.6 (range 20-96) years fulfilled the inclusion criteria. The annual incidence per million of the population (95% CI) was estimated to be 9.8 (7.4-12.2) for WG, 10.1 (7.7-12.6) for MPA and 0.9 (0-1.7) for both CSS and PAN. The highest incidence was found in patients aged >or=75 years (79.1/million). The 1- and 5-year survival rates were 87.8 and 71.6% for all patients, but lower for MPA (80 and 55%) compared with WG (95 and 83%; P = 0.001), although the difference was not significant in the multivariate analysis. The SMR was 2.77 (95% CI 2.02, 3.71) for all patients. CONCLUSIONS The incidence of WG and MPA was equal in our district, but there was a difference in survival rates related to age and renal function. A progressive increase in age-specific incidence rates was observed.

Risk for Cardiovascular Disease Early and Late After a Diagnosis of Giant-Cell Arteritis: A Cohort Study

Context Whether patients with giant-cell arteritis (GCA) are at increased risk for major cardiovascular events is not known. Contribution This population-based cohort study found increased risks for myocardial infarction, cerebrovascular accident, and peripheral vascular disease among patients with GCA, particularly in the first month after the diagnosis of GCA. Implication Clinicians should be alert to the potential for major cardiovascular events in patients with GCA. Whether preventative practices should be changed requires further study. The Editors Giant-cell arteritis (GCA) is a large-vessel vasculitis that has predilection for large and medium-sized arteries (1, 2). It can result in ischemic blindness (3, 4), and the mainstay of treatment is high doses of glucocorticoids for substantial periods. Imaging studies have described a high prevalence of large-artery stenoses and aneurysms in cohorts of patients with GCA (5, 6), but studies exploring the association of GCA with clinically important cardiovascular events have provided conflicting results (7, 8). A large population study from Canada of 1100 patients with GCA showed an increase in vascular events (coronary heart disease, stroke, peripheral artery disease, aneurysm, and dissection) compared with randomly selected reference participants from the same population (hazard ratio [HR], 2.1 [95% CI, 1.5 to 3.0] after limited adjustment for potential risk factors [medication use for hypertension and hyperlipidemia]) (7). In contrast, a preliminary report from a large cohort study in the United States using hospital discharge diagnoses of GCA in 4807 patients found an increase in thoracic aortic aneurysms (HR, 5.2 [95% CI, 1.5 to 9.0]) and a minimally increased risk for strokes (HR, 1.29 [CI, 1.15 to 1.45]), but not for other atherosclerotic disease (coronary heart disease, peripheral artery disease, or aortic abdominal aneurysm) compared with 19228 reference participants (8), with limited adjustment for cardiovascular risk factors. A few studies have suggested that traditional cardiovascular risk factors are associated with occurrence and complications of GCA (912). Therefore, information on cardiovascular risk factors is important when the association of GCA with cardiovascular disease is explored. The objective of this study was to determine the association between GCA and incident cardiovascular disease, defined as myocardial infarction (MI), cerebrovascular accident (CVA), or peripheral vascular disease (PVD), in an unselected population cohort with information on risk factors for cardiovascular disease. Methods Data Source Data were obtained from The Health Improvement Network (THIN), an electronic database derived from general practices in the United Kingdom that includes data on approximately 7.3 million patients (13). Database elements are obtained from visits with general practitioners, specialists, and from hospitalizations. Data on diagnoses (14), prescription medications, height, weight, smoking status, vaccinations, and other variables are entered into the THIN database by primary care physicians during clinical visits. This study was judged to be exempt from review by the Institutional Review Board at Boston University Medical Center and was approved by the THIN Scientific Review Committee. Study Design We performed a matched cohort study to examine the relation of patient with incident GCA to risk for MI, CVA, and PVD. Specifically, for each GCA, we selected up to 5 individuals without GCA at the time that the patient with GCA was diagnosed, matched by age, sex, and time of entry into the THIN database. Patients with cardiovascular disease (MI, CVA, or PVD) at baseline were excluded. GCA Definition Patients with GCA were those who had a diagnosis of GCA, temporal arteritis, or Horton disease that appeared at least 1 year after the patient was entered into the THIN database and who received and used a prescription for glucocorticoids. We defined glucocorticoid use as 2 prescriptions for oral glucocorticoids, the first within 6 months of the date of GCA diagnosis and the second within 6 months of the first prescription. The database used for analysis was compiled in 2012. Because historical diagnoses may be erroneously recorded as having occurred on the date of patient enrollment or the date when a general practice begins to use the database software, patients with incident cases were included only if GCA was first diagnosed at least 12 months after their records were computerized. Because GCA is exceptionally rare among persons younger than 50 years, we excluded persons in this age group from the analysis. In a supplemental analysis, we used a more stringent definition of GCA that required 10 or more prescriptions of glucocorticoids. Covariate Assessment We obtained information on cardiovascular risk factors as follows. Information on smoking status was obtained from the codes for smoking and smoking history. A categorical variable with the values current smoker, former smoker, or never smoker was created. Hypertension was handled as a dichotomous variable defined as the presence or absence of any of the following diagnoses: hypertension, essential hypertension, high blood pressure, malignant essential hypertension, benign essential hypertension, systolic hypertension, or diastolic hypertension. We obtained data on total cholesterol level in millimoles per liter and used this as a continuous variable. Diabetes mellitus was handled as a dichotomous variable defined as a diagnosis of diabetes mellitus or any of its subcodes or an outpatient prescription code for any form of insulin, sulfonylureas, or other drugs used to treat diabetes (excluding biguanides). Body mass index (BMI) was obtained from a corresponding code in the medical record. Only data on covariates that were recorded in the THIN database before patients contribution of follow-up time were included in the analysis. Assessment of Medications Used for Cardiovascular Disease We assessed baseline use of the following medications commonly prescribed to treat cardiovascular disease: antiplatelet agents, -blockers, nitrates, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). We defined medication use as 1 or more outpatient prescription codes for one of these medications. Follow-up and Outcomes Definitions Data collected from 1 January 1990 through 1 June 2010 were used for this study. We followed patients with GCA from the date of diagnosis and reference participants from the matched (index) date until occurrence of any cardiovascular event, death, migration of the THIN database, or 1 June 2010, whichever came first. Incident MI was defined as the presence of any of several diagnostic codes pertaining to MI, including myocardial infarction, heart attack, and codes pertaining to a specific anatomical site of the myocardium or specified pattern on an electrocardiogram. Incident PVD was defined as any of the following diagnoses: peripheral ischemic vascular disease, other specified peripheral vascular disease NOS, other peripheral vascular disease, or peripheral vascular disease. Incident CVA was defined as the first appearance of any of the following diagnoses: CVA unspecified, stroke unspecified, cerebrovascular accident unspecified, middle cerebral artery syndrome, anterior cerebral artery syndrome, posterior cerebral artery syndrome, brainstem stroke syndrome, cerebellar stroke syndrome, pure motor lacunar syndrome, pure sensory lacunar syndrome, or left- or right-sided CVA. Patients who had 1 type of cardiovascular event were censored in the analyses for the other types. Statistical Analysis We compared the characteristics of patients with GCA and reference participants by using the t test for continuous variables and a chi-square test for categorical variables. Person-years of follow-up for each patient were computed as the time from the index date to the end of follow-up. We calculated incidence rates of each outcome event for each group by dividing the number of cases of each outcome variable by the number of person-years. The associations between GCA and study outcomes are expressed as incidence rate ratios with 95% CIs. We plotted the cumulative incidence rate of each outcome variable for individuals with and without GCA and accounted for the competing risk for the other outcomes. We used the Markov-chain Monte Carlo method (15) to impute missing data on BMI, cholesterol level, and smoking status under the assumption that data were missing at random (MAR). Because there was a substantial amount of missing data on cholesterol level (>50%), 50 data sets with imputed data were created and data for the following variables were used for imputation of missing variables: age, sex, GCA status, smoking status, hypertension, diabetes mellitus, cholesterol level, BMI, and outcome. Because the MAR assumption was unverifiable, we performed the analysis using both the imputed data sets and those restricted to patients with complete data. We fitted Cox proportional hazards models to separately determine the relation of GCA to cardiovascular disease (MI, CVA, or PVD). In the multivariate Cox proportional hazards models, we adjusted for age, sex, smoking, hypertension, diabetes mellitus, BMI, and total cholesterol level. In the adjusted analysis, the effect of GCA on study outcomes is expressed with HRs with 95% CIs. The assumption of proportional hazards between patients with and without GCA was evaluated by a visual inspection of a diagnostic plot of the log of the minus log survival against log time and by testing an interaction term between time and GCA status for statistical significance, with a 2-sided P value less than 0.05 indicating statistical significance. In cases where the proportional hazards assumption was violated, series of average HRs for increasingly longer periods of follow-up are presented (16). We conducted 3 sensitivity analyses. First, to account f

Rituximab for the treatment of eosinophilic granulomatosis with polyangiitis (Churg–Strauss)

Background Conventional treatment of eosinophilic granulomatosis with polyangiitis (EGPA) (Churg–Strauss) with glucocorticoids, with or without additional immunosuppressive drugs, is limited by partial efficacy, frequent toxicity and a high relapse rate. Rituximab is a licensed treatment for granulomatosis with polyangiitis and microscopic polyangiitis and is of potential benefit to patients with EGPA. Methods Patients with EGPA who received rituximab as single or repeated courses were identified from four vasculitis centres. Standardised data collection was performed, including disease activity status and adverse events, at the time of initial treatment and after 6 and 12 months. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and partial response as a ≥50% reduction in BVAS compared with baseline. Results 41 patients (21 women) with EGPA treated with rituximab between 2003 and 2013 were identified. 15 (37%) had refractory, 21 (51%) relapsing and 5 (12%) new onset disease. 19 received a single course and 22 received repeat-dose rituximab to prevent relapse. By 6 months, 83% improved with remission in 34% and partial response in 49%, and by 12 months 49% were in remission and 39% had a partial response. Prednisolone doses decreased in all patients by 6 and 12 months. Antineutrophil cytoplasmic antibody positivity at baseline was associated with a higher remission rate at 12 months. Adverse events included 15 infections (6 were severe). Conclusions The treatment of EGPA with rituximab resulted in high rates of improvement and reduced requirement of prednisolone. Rituximab may be considered for the treatment of EGPA.

Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis

It is now 25 years since the first European studies on vasculitis--the anti-neutrophil cytoplasmic antibody (ANCA) standardization project. Over that period of time, there have been major developments in the classification of the vasculitides, which has permitted the conduct of high-quality epidemiology studies. Studying the epidemiology of rare diseases such as the ANCA-associated vasculitides (AAV) poses considerable challenges to epidemiologists. The first is the need for a clear definition of a case with good differentiation from similar disorders. The second is case capture. The vasculitides are rare, and therefore, a large population is required to determine the incidence and prevalence, and this poses questions of feasibility. A large population increases the risk of incomplete case detection but permits a reasonable number of cases to be collected in a practicable time frame, whereas a smaller population requires a much longer time frame to collect the necessary cases, which may also not be feasible. Statistical methods of capture-recapture analysis enable estimates to be made of the number of missing cases. The third is case ascertainment. The AAV are virtually always managed in secondary care, and therefore, hospital-based case ascertainment may be appropriate. Fourthly, the rarity of the conditions makes prospective case-control studies investigating risk factors difficult to conduct because the population size required to achieve statistical confidence is in excess of that which is readily available. Thus, much of the data on risk factors are derived from retrospective studies with inherent potential bias.

Incidence and mortality rates of biopsy-proven giant cell arteritis in southern Sweden

Objectives To study the epidemiology and mortality in patients with biopsy-proven giant cell arteritis (GCA) in southern Sweden. Methods The study area was the County of Skåne. Patients with a positive temporal artery biopsy between 1997 and 2010 were identified using a regional register and a structured review of all histopathology reports. Standardised mortality ratios (SMR) were calculated using data for the Swedish population as the reference. Results There were 840 patients with biopsy-proven GCA (626 women). The annual incidence rate per 100 000 inhabitants aged ≥50 years was 14.1 (95% CI 13.1 to 15.0); 7.7 (6.7 to 8.7) for men and 19.6 (18.1 to 21.1) for women, without seasonal variations. The incidence increased with age, with estimates of 2.0, 11.8, and 31.3 per 100 000 in the age groups 50–60, 61–70, 71–80 years, respectively (p<0.001). The age-standardised and sex-standardised incidence rate decreased from 15.9/100 000 in 1997–2001 to 13.3/100 000 in 2007–2010 (p=0.026). Two hundred and seventy-nine patients (207 women) died during the observation period. Mortality was significantly increased over the first 2 years after GCA diagnosis (SMR 1.52 (95% CI 1.20 to 1.85)), but not with longer follow-up. The estimated excess mortality was greater in women and in patients aged ≤70 years at diagnosis. Conclusions In this large population-based study of biopsy-proven GCA from southern Sweden, the incidence of GCA may have decreased over time. Short-term mortality was increased, in particular among those diagnosed at ≤70 years of age, but long-term survival was not impaired.

Incidence, prevalence and clinical characteristics of Behçet’s disease in southern Sweden

OBJECTIVE To study the incidence, prevalence and clinical characteristics of Behçets disease (BD) in a defined population in southern Sweden. METHODS The study area consists of three health-care districts with an adult population (≥15 years) of 809 317 on 1 January 2011 (25% of non-Swedish ancestry), situated in Skåne, the southernmost county in Sweden. Patients were identified using clinical registries in all the five hospitals within the study area. Only patients fulfilling the International Study Group criteria for diagnosis of BD were included. RESULTS Forty patients (13 women) fulfilling the diagnosis criteria for BD (70% of non-Swedish ancestry) were identified. The point prevalence of BD on 1 January 2011 was 4.9/100,000 adults (95% CI 3.4, 6.5) and was higher among the population of non-Swedish ancestry (13.6 vs 2.0/100,000, P < 0.001), and higher among men (6.8 vs 3.2/100,000, P = 0.019). There were 20 incident cases (diagnosed in Sweden between 1997 and 2010). The annual incidence rate was 0.2/100,000 adults (95% CI 0.1, 0.3) and was higher among the population of non-Swedish ancestry (0.6 vs 0.1/100,000, P < 0.001). The incidence was 0.3/100,000 adults in men and 0.1/100,000 in women, P = 0.143. During the course of the disease, 100% of the patients developed oral ulceration, 80% genital ulcers, 88% skin lesions, 53% eye disease, 40% arthritis/arthralgia and 20% venous thrombosis. CONCLUSION The prevalence of BD is higher in Sweden than previously reported, mainly due to immigration. The incidence of BD remains elevated for immigrants from high-prevalence regions even long after settling in Sweden.

A population-based study showing better renal prognosis for proteinase 3 antineutrophil cytoplasmic antibody (ANCA)-associated nephritis versus myeloperoxidase ANCA-associated nephritis.

Objective. Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) is usually differentiated based on clinical phenotypes, but recent data indicate that myeloperoxidase (MPO)-AAV is genetically distinct from proteinase 3 (PR3)-AAV. We reviewed a population-based cohort of AAV, focusing on differences in clinical and laboratory characteristics and to compare renal outcome between MPO-ANCA and PR3-ANCA nephritis. Methods. All new cases of AAV diagnosed between 1997 and 2009 in a geographically defined area in southern Sweden were retrieved using a validated search algorithm. Data were collected from time of diagnosis and end of followup. Renal and patient survival were analyzed according to ANCA serotype. Results. During the study period, 201 patients were diagnosed with AAV, 98 tested positive for PR3-ANCA, and 85 for MPO-ANCA. Patients with PR3-ANCA were younger, had significantly higher inflammatory activity, and had a larger number of organs involved at diagnosis, but nephritis was more prevalent among patients with MPO-associated (72/85; 85%) versus PR3-associated disease (67/98, 68%). When comparing only patients with ANCA-associated nephritis, those with MPO-ANCA were more likely to develop endstage renal disease (n = 27, 38%) than those with PR3-ANCA (n = 10, 15%), p = 0.003. The risk remained significantly elevated after adjusting for sex, age, and s-creatinine level at diagnosis (HR 2.64; 95% CI 1.25–5.58; p = 0.003). There were no significant differences in mortality rates between the 2 groups. Conclusion. The outcome in this population-based cohort indicates that among AAV patients with nephritis, renal prognosis is better in the PR3-ANCA group, even after adjustment for sex, age, and renal function at diagnosis.

Outcome and Treatment of Elderly Patients with ANCA-Associated Vasculitis

BACKGROUND AND OBJECTIVES ANCA-associated vasculitis is commonly found in elderly patients, but there are few data concerning outcome and treatment in the highest age groups. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Consecutive patients (N=151) presenting between 1997 and 2009 were retrospectively included from local registries in six centers in Sweden, the United Kingdom, and the Czech Republic if diagnosed with microscopic polyangiitis or granulomatosis with polyangiitis at age ≥75 years during the study period. Patients were followed until 2 years from diagnosis or death. Data on survival and renal function were analyzed with respect to age, sex, ANCA specificity, renal function, C-reactive protein, comorbidities, and Birmingham Vasculitis Activity Score at diagnosis as well as treatment during the first month. RESULTS Median follow-up was 730 days (interquartile range, 244-730). Overall 1-year survival was 71.5% and 2-year survival was 64.6%. Older age, higher creatinine, and lower Birmingham Vasculitis Activity Score were associated with higher mortality in multivariable analysis. Patients who were not treated with standard immunosuppressive therapy had significantly worse survival. Renal survival was 74.8% at 1 year. No new cases of ESRD occurred during the second year. High creatinine at diagnosis was the only significant predictor of renal survival in multivariable analysis. CONCLUSIONS ANCA-associated vasculitis is a disease with substantial mortality and morbidity among elderly patients. This study showed a better prognosis for those who received immunosuppressive treatment and those who were diagnosed before having developed advanced renal insufficiency.

Takayasu Arteritis in Southern Sweden

Objective. To study the epidemiology and clinical characteristics of Takayasu arteritis (TA) in southern Sweden. Methods. The study area is situated in Skåne, the southernmost county in Sweden (total population December 2011: 983,419, 50.5% women). Patients were identified using clinical registries in all the 5 hospitals and private rheumatology clinics within the study area between the years 1997 and 2011. The diagnosis of TA was confirmed by medical records review. Only patients fulfilling the 1990 American College of Rheumatology classification criteria were included. Results. Thirteen patients (all women) were identified. The median age at diagnosis was 23 years [interquartile range (IQR) 16–38]. Ten patients were diagnosed between 1997 and 2011. The annual incidence rate was estimated to 0.7/million inhabitants (95% CI 0.3–1.2) and 1.5/million among women (95% CI 0.6–2.4). Patients were followed for a median of 9 years (IQR 4–17.5). As of January 1, 2012, all 13 patients were alive and living within the study area. The point prevalence per million inhabitants was 13.2 (95% CI 6.0–20.4), and 26.2 among women (95% CI 11.9–40.4). Subclavian arteries were the most commonly affected vessels. Organ damage was common, affecting all patients. Seven pregnancies resulting in 5 live births and 2 abortions were registered after the diagnosis of TA. Conclusion. The incidence of TA in Sweden is comparable to recently reported rates from other European studies, while the prevalence is higher than previously reported. The prognosis of TA is good, but the rate of damage is high.

The extent and pattern of organ damage in small vessel vasculitis measured by the Vasculitis Damage Index (VDI)

Objectives: To assess the extent and pattern of irreversible organ damage in patients with Wegeners granulomatosis (WG), microscopic polyangiitis (MPA), polyarteritis nodosa (PAN), and Churg–Strauss syndrome (CSS) by a cross‐sectional point prevalence study within a defined geographical area. Methods: The Vasculitis Damage Index (VDI) was recorded for 86 prevalent cases, classified as 46 patients with WG, 27 with MPA, nine with PAN, and four with CSS from a defined population in southern Sweden, with a median age of 64.8 years and a median disease duration of 9 years. The VDI was determined for all patients at the day of point prevalence (pp), 1 January 2003. Results: The median VDI score was 3 [interquartile range (IQR) 2–5] for all patients: 3 (2–4) for WG, 3 (1.5–4.5) for MPA, 5 (2–6) for PAN, and 1.5 (0.75–2.75) for CSS. Only 9% of patients had not been assigned a single item of damage. The most common damage was cardiovascular, followed by renal, neuropsychiatric, ear nose and throat (ENT), and musculoskeletal. Major vascular and treatment‐related damage was associated with advanced age whereas ENT damage was more prevalent in younger patients. There was an almost complete separation between ENT damage and cardiac and renal damage with only two out of the 22 patients assigned ENT damage having experienced renal damage; none had been assigned cardiac damage. Patients with cardiac damage had significantly higher damage rates. Conclusions: Damage remains an important problem for patients with systemic vasculitis despite effective remission‐inducing drugs. Only a small fraction of patients are unmarked by their disease.