The temporal association between adverse drug reactions and antirheumatic drugs utilisation in Western Australia: a retrospective study from real-world data (1995-2015).

BACKGROUND/OBJECTIVES: Adverse drug reactions (ADRs) can result in morbidity, mortality, and higher healthcare costs. Given the limited information available on ADRs associated with antirheumatic medications, this study aims to analyse and compare ADR reporting for these drugs in the pharmacovigilance datasets of Western Australia (WA) and the United States (US). METHODS: Therapeutic Goods Administration provided WA pharmacovigilance data of selected antirheumatic drugs to from 1995 to 2015. The proportional reporting ratio (PRR) for WA case reports was compared to corresponding USA pharmacovigilance data by assessing the disproportionality of each ADR. clinically significant or true ADRs were determined using the Evans 2001 criteria (n > 2, chi-square > 4, PRR > 2). RESULTS: A total of 232 reports were found in WA, mostly on sixty-nine women aged 45 to 69. Methotrexate, leflunomide, azathioprine, sulfasalazine, and infliximab had the highest reported ADRs, related to gastrointestinal disorders. Patients who used biological agents in WA had 2.7 times the likelihood of reporting true ADRs compared to conventional antirheumatic drugs. The ADR rates in the two datasets were comparable over the study period. CONCLUSIONS: The PRR values of ADRs were consistent between WA and US databases. Methotrexate and infliximab use were commonly associated with ADR reports in WA females, with incidence rates comparable to the US; while patients using biological agents were more likely to report true ADRs than those on conventional antirheumatic drugs in WA.

Cancer Risk and Mortality in Hospitalized Patients With Idiopathic Inflammatory Myopathies in Western Australia.

OBJECTIVE: To compare cancer incidence, type, and survival between patients with idiopathic inflammatory myopathies (IIMs) in Western Australia (WA) and the general population. METHODS: Administrative health data for hospitalized patients with incident IIM (n = 803, 56.5% female, median age 62.0 yrs), classified by a validated algorithm as polymyositis (PM; 36.2%), dermatomyositis (DM; 27.4%), inclusion body myositis (IBM; 17.1%), overlap myositis (OM; 10.7%), and other IIM (8.6%), were linked to WA cancer and death registries for the period of 1980 to 2014. Cancer incidence rates (CIRs) before and after IIM diagnosis as well as cancer mortality were compared with age-, sex-, and calendar year-matched controls (n = 3225, 54.9% female, median age 64 yrs) by rate ratios (RRs) and Kaplan-Meier survival estimates. RESULTS: The prediagnosis CIR was similar for patients with IIM and controls (6.57 vs 5.95; RR 1.11, 95% CI 0.88-1.39) and for patients evolving to DM (n = 220) or other IIM subtypes (6.59 vs 6.56; RR 1.01, 95% CI 0.38-3.69). During follow-up, CIR was higher for all DM (4.05, 95% CI 3.04-5.29), with increased CIR for lung cancer vs controls (1.05 vs 0.33; RR 3.18, 95% CI 1.71-5.47). Cancer post diagnosis shortened life span by 59 months for patients with IIM (103 vs 162 months, P < 0.01), but reduced survival rates were observed only in patients with DM and IBM. CONCLUSION: Cancer risk was not increased prior to IIM, but CIR for lung cancer was increased following DM diagnosis. As cancer reduced survival only in patients with DM and IBM, these data support a strategy of limited cancer screening in IIM.

Population-wide long-term study of incidence, renal failure, and mortality rates for lupus nephritis.

OBJECTIVE: Given limited regional data, we investigate the state-wide epidemiology, renal and patient outcomes for lupus nephritis (LN) in Western Australia (WA). METHODS: Patients hospitalized with incident SLE (≥2 diagnostic codes in the state-wide WA Health Hospital Morbidity Data Collection) in the period 1985-2015 were included (n = 1480). LN was defined by the presence of glomerulonephritis and/or raised serum creatinine. Trends over three study decades for annual incidence rate (AIR)/100.000 population, mortality (MR), and end-stage renal disease (ESRD) rates/100 person years were analyzed by least square regression and compared with a matched control group (n = 12 840). RESULTS: Clinical evidence of LN developed in 366 SLE patients (25.9%) after a median disease duration of 10 months (IQR 0-101) with renal biopsy performed in 308 (84.2%). The AIR for LN (0.63/100.000) did not change significantly over time (R2 = .11, p = .85), while point prevalence reached 11.9/100.000 in 2015. ESRD developed in 14.1% (n = 54) of LN patients vs. 0.2% in non-LN SLE patients and 0.05% in controls (all p ≤ 0.01). ESRD rates increased over time in LN patients (0.4 to 0.7, R2 = .52, p = .26). The odds ratio for death was 8.81 (CI 3.78-22.9) for LN and 6.62 (CI 2.76-17.9) for non-LN SLE patients compared to controls and MR for LN patients increased over time (1.3 to 2.2, R2 = .84, p = .26). CONCLUSIONS: The incidence rate of LN in WA remained unchanged over 30 years. A lack of improvement in renal failure and mortality rates illustrates the pressing need for better long-term treatment options and/or strategies in LN.

Mortality Trends Among Patients with Rheumatoid Arthritis in Western Australia.

INTRODUCTION: With scarce comparative data on mortality in Australian patients with rheumatoid arthritis (RA), we investigated temporal changes in standardized mortality rates for patients with RA using longitudinal linked population-wide health data in Western Australia (WA) over the period 1980 to 2015. METHODS: The study included 17,125 patients with a first-time hospital contact for RA (ICD-10-AM M05.00-M06.99 and ICD-9-AM 714.00-714.99) in the study period. Standardized mortality rate ratios (SMRRs) for the RA cohort versus the WA general population was estimated using direct age standardization. We analyzed temporal trends over with dates and causes provided by the WA Death Registry. RESULTS: During 356,069 patient-years of follow-up, a total of 8955 (52%) deaths occurred in the RA cohort. The SMRR was 2.24 (95% CI 2.15-2.34) in males and 3.09 (95% CI 3.00-3.19) in females over the study period. SMRR decreased since 2000 to 1.59 (95% CI 1.39-1.81) for the period 2011-2015. Median survival was 26.80 years (95% CI 26.30-27.30), where age and comorbidity independently increased the risk of death. The leading causes of deaths were cardiovascular diseases (26.60%), cancer (16.80%), rheumatic diseases (5.80%), chronic pulmonary disease 491 (5.50%), dementia (3.00%), and diabetes 235 (2.6%). CONCLUSIONS: The mortality rate in patients with RA in WA has decreased but remains 1.59-times higher than in community counterparts, suggesting that there is room for further improvement. Comorbidity is the main modifiable risk factor to further reduce mortality in patients with RA.

Systemic juvenile idiopathic arthritis: frequency and long-term outcome in Western Australia.

Systemic juvenile idiopathic arthritis (S-JIA) is a rare but potentially life threatening autoinflammatory condition of childhood. Given the limited data on S-JIA from the Australasian region, we investigated the epidemiological characteristics and long-term disease outcome in S-JIA. All hospitalised patients under the age of 16 years registered with ICD-10-AM code M08.2 in in the period 1999-2014 were identified in longitudinally linked administrative health data across all Western Australian (WA) hospitals. Incidence and point prevalence estimate were per 100,000 population with Poisson regression to analyse the incidence trend. Readmissions with S-JIA as primary diagnosis were considered flares with rates for flare and other complication reported per 100 person years with 95% confidence intervals (CI). Annual S-JIA incidence was 0.61/100,000 (CI 0.28-1.25) (46 incident cases, 71.7% girls, median age 6.5 years) and stable over time as S-JIA point prevalence reached 7.15/100,000 (CI 5.29-7.45) at the end of study. Most incident cases were diagnosed in winter and spring, but documented preceding infections were rare. During a median follow-up of 8 years, disease flares occurred in 24% of patients with higher flares rate in boys (58.3; CI 44.5-74.9) than girls (14.7; CI 9.9-20.9). No deaths occurred and arthroplasty was the main, but uncommon S-JIA complication (4%). However, readmission (86.3; CI 76.4-97.2) and ED visit (73.3; CI 64.2-83.4) rates for illnesses other than S-JIA were substantial. S-JIA is as rare in WA as in other regions and while s-JIA incurred no deaths in the era of biologics, it associated with a significant long-term burden of (co-) morbidity.

Trends in Hospitalization for Tuberculosis and Other Opportunistic Infections in Australian Patients with Inflammatory Joint Diseases.

OBJECTIVE: As immune-modulating therapy has become the standard of care for idiopathic inflammatory joint diseases (IJD), we investigated whether this has changed the rates for hospitalization with opportunistic infections (OI). METHODS: Administrative longitudinal state-wide health data identified patients hospitalized at least twice with diagnostic codes for rheumatoid arthritis (RA, n = 7730), psoriatic arthritis (PsA, n = 529) or axial spondylarthritis (AS, n = 1126) in Western Australia in the period 1985-2015. Overall incidence rates/1000 person-years (IR with 95% CI) for microbiologically confirmed OI (mycobacterial, fungal, and viral infections) during 180,963 person-years were analyzed across 10-year periods with IR trend rates analyzed by least square regression (R2) for all IJD categories. RESULTS: A total of 2584 OI occurred with higher IR rates observed in RA (15.34, CI 14.71-15.99) than PsA (8.73, CI 7.14-10.56) and AS (10.88, CI 9.63-12.24) patients (p < 0.001). IR rates were highest for Candidiasis across all three IJD categories (IR 10.0 vs. 6.32 vs. 6.88, respectively), while Varicella-zoster (VZV) was most frequent non-candida OI (IR 2.83.0 vs. 1.50 vs. 1.49, respectively) followed by mycobacterial (IR 1.14 vs. 0.08 vs. 0.24, respectively) and other mycotic infections (IR 0.60 vs. 0.58 vs. 0.86, respectively). Over time, the IR for tuberculosis and pneumocystosis decreased and remained stable for VZV infections in RA patients, but IR for all other OI increased across all disease categories. OI admission associated with 6.5% (CI 5.6-7.5) in-hospital mortality. CONCLUSIONS: Despite decreasing admission rates for tuberculosis and pneumocystosis in RA patients, an overall increase in mycotic and viral infection rates over time was seen across all three IJD. Together with a significant case fatality rate, this indicates continued efforts are needed to improve OI prevention in the management of IJD patients.

Mortality Rates in Patients With Ankylosing Spondylitis With and Without Extraarticular Manifestations and Comorbidities: A Retrospective Cohort Study.

OBJECTIVE: To examine mortality rates in hospitalized patients with ankylosing spondylitis (AS) and the association of extraarticular manifestations (EAMs) and comorbidities with mortality rates. METHODS: This study was a retrospective, population-based cohort study using linked administrative data from patients with AS who were hospitalized (n = 1791) and patients in a matched comparison group (n = 8955). Mortality data for patients were obtained from the Western Australia Death Register. The presence of EAMs and comorbidities was identified from hospital records. Mortality rates were compared between the 2 groups using Cox proportional hazard models overall and stratified by a history of EAMs, comorbidities, and smoking status. RESULTS: Crude mortality rates were significantly higher among patients with AS than among patients in the comparison group (hazard ratio [HR] 1.85, 95% CI 1.62-2.12), with excess mortality in the AS group associated with cardiovascular disease (CVD; HR 5.32, 95% CI 3.84-7.35), cancer (HR 1.68, 95% CI 1.27-2.23), external causes (HR 3.92, 95% CI 2.28-6.77), and infectious diseases (HR 25.92, 95% CI 7.50-89.56). When patients were stratified by history of EAMs, CVD, and smoking, the risk of mortality was elevated in patients both with and without each risk factor. Among patients with AS, histories of CVD (HR 6.33, 95% CI 4.79-8.38), diabetes (HR 2.81, 95% CI 1.99-3.95), smoking (HR 1.49, 95% CI 1.18-1.89), and EAMs (HR 1.62, 95% CI 1.24-2.11) were associated with an increased risk of mortality. CONCLUSION: The presence of comorbidities, EAMs, and smoking contributes to an increased risk of all-cause mortality among patients with AS who are hospitalized compared to patients in the comparison group. These results support the need to prevent or reduce the occurrence of comorbidities and smoking in patients with AS.

Total Hip Replacement in Patients with Rheumatoid Arthritis: Trends in Incidence and Complication Rates Over 35 Years.

INTRODUCTION: Advances in rheumatoid arthritis (RA) management have made disease remission achievable. We evaluated trends in total hip replacement (THR) and postoperative outcomes in patients with RA in Western Australia (WA) over more than three decades. METHODS: This was a retrospective analysis of routinely collected prospective data from a state-wide registry containing longitudinally linked administrative health data based on International Classification of Diseases (ICD) diagnostic and procedural codes. We included patients with two or more diagnostic codes for RA (between 1980 and 2015) and studied THR incidence rates (THR IR) and complication rates (revision, peri-prosthetic fracture, infection, venous thrombosis, and mechanical loosening). Survival rates were estimated by Kaplan-Meier method and predictors analyzed by Cox regression. RESULTS: We followed 9201 RA patients over 111,625 person-years, during which 1560 patients (16.9%) underwent THR. From 1985 to 2015, THR IR (per 1000 RA patient-years) decreased from 20.8 (95% CI 20.1-21.5) to 7.3 (95% CI 7.2-7.5), and 5-year THR-free survival increased from 84.3 to 95.3% (1980-2015). Ten-year prosthetic survival was 91.2%. Complication rates in the first 5 years post-THR decreased significantly from 13.1 to 3.7% (p < 0.001). Mechanical complications such as loosening and periprosthetic fracture rates decreased significantly (> 35%, P < 0.05), while infection and revision did not change over the observation period (p > 0.05). CONCLUSIONS: Over the last 30 years in RA patients, THR IR and mechanical complication rates decreased significantly, but the medical complication of infection has not changed significantly.

Septic Arthritis in Children: A Longitudinal Population-Based Study in Western Australia.

OBJECTIVE: To describe the incidence, risk factors and long-term outcomes in children hospitalised with septic arthritis (SA) in Western Australia (WA). METHODS: We extracted state-wide longitudinally linked administrative health data for patients aged < 16 years with a first diagnostic code of 711.X (ICD9-CM) and M00.X (ICD10-AM) in WA in the period 1990-2010. Annual incidence rates (AIR) per 100,000 with 95% confidence intervals (CIs), prior conditions during a median lookback period of 63.2 [interquartile range (IQR) 19.8-117.1] months and outcomes, including standardised mortality rates (SMR), during a median follow-up of 10 years are reported. RESULTS: A total of 891 patients [62% male, median age 6.4 (IQR 1.9-10.6) years with 34% aged < 3 years] were admitted for SA during the observation period. The overall AIR (per 100,000) was 9.85 (95% CI 4.79-14.41), and was higher in Indigenous Australians [34.9 vs. 5.5 (non-Indigenous), p < 0.001] and in males [11.9 vs. 7 (females), p < 0.01]; AIR showed no temporal or seasonal variation. Knees (43.9%), hips (34.6%) and ankles (13.3%) were most frequently affected, with Staphylococci predominant (49%) in patients with positive cultures (41.5%). Prior infection(s) (40.4%) and respiratory disease (7%) were the main pre-existing morbidities. Median hospital stay was 4.0 (IQR 2-8) days, with 1.9% requiring admission to the intensive care unit and 10.4% requiring readmission within 30 days. During follow-up, 26 patients (3.1%) developed osteomyelitis, nine patients were diagnosed with osteoarthrosis (1.1%) and five patients (0.6%) underwent joint replacement. Female patients developed other serious infections more often than male patients (40.5 vs. 27.1%, p < 0.01), as well as other comorbidities (Charlson Comorbidity Index > 0: 34.6 vs. 27.2%, p = 0.02), including diabetes (4.2 vs. 0%; p = 0.001), cardiovascular events (4.2 vs 1.4%, p = 0.002) and chronic arthritis (1 vs. 0%, p = 0.05). The crude mortality rate was low (0.3%), with 99.4% survival at 180 months and no increase in the SMR. CONCLUSIONS: The incidence of SA in children in WA did not change over the 20-year observation period. SA did not lead to excess mortality, but bone and joint complications developed in 5% of patients. The high propensity to comorbid conditions in this young cohort suggests an underlying role of comorbidity in SA development.

As more children are living with complex and chronic conditions, we investigated whether children in Western Australia (WA) have become more prone to joint infections. During a 20-year observation period we collected health data for all children admitted to any hospital in the state with an infected joint and recorded their health outcomes. We found that joint infection occurs in nearly ten out of 100,000 children each year, but we saw no change in the frequency over time. We did observe higher rates in Indigenous children (35/100,000) than in non-indigenous children (6/100,000) but found no noticeable influence of the seasons on the frequency of joint infections. Knees, hips and ankles were most often affected, and 15% had additional bone infection. Children needed to be treated in hospital for 4­5 days, and only a small minority (1.2%) were so ill they needed intensive care. Joint infections led to chronic, long-term complications in about 5% of patients, but we found no evidence that joint infections increased the risk of death compared to children in the general population.

The Prevalence of Rheumatoid Arthritis: A Systematic Review of Population-based Studies.

OBJECTIVE: To estimate the prevalence of rheumatoid arthritis (RA) from international population-based studies and investigate the influence of prevalence definition, data sources, classification criteria, and geographical area on RA prevalence. METHODS: A search of ProQuest, MEDLINE, Web of Science, and EMBASE was undertaken to identify population-based studies investigating RA prevalence between 1980 and 2019. Studies were reviewed using the Joanna Briggs Institute approach for the systematic review and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Sixty studies met the inclusion criteria. There was a wide range of point prevalence reported (0.00-2.70%) with a mean of 0.56% (SD 0.51) between 1986 and 2014, and a mean period prevalence of 0.51% (SD 0.35) between 1955 and 2015. RA point and period prevalence was higher in urban settings (0.69% vs 0.48%) than in rural settings (0.54% vs 0.25%). An RA diagnosis validated by rheumatologists yielded the highest period prevalence of RA and was observed in linked databases (0.80%, SD 0.1). CONCLUSION: The literature reports a wide range of point and period prevalence based on population and method of data collection, but average point and period prevalence of RA were 51 in 10,000 and 56 in 10,000, respectively. Higher urban vs rural prevalence may be biased due to poor case findings in areas with less healthcare or differences in risk environment. The population database studies were more consistent than sampling studies, and linked databases in different continents appeared to provide a consistent estimate of RA period prevalence, confirming the high value of rheumatologist diagnosis as classification criteria.

The Risk and Consequences of Vertebral Fracture in Patients with Ankylosing Spondylitis: A Population-based Data Linkage Study.

OBJECTIVE: To compare the long-term prevalence, incidence, and outcomes of vertebral fracture (VF) between ankylosing spondylitis (AS) patients and matched controls, including the role of extraarticular manifestations (EAM) and osteoporosis. METHODS: This was a statewide observational study using linked health data for 2321 patients with AS and 22,976 controls presenting to hospital from 1980 to 2015. Data were analyzed using incidence rates (per 1000 person-yrs) and ratios (IRR), multivariable Cox proportional hazards regression, and Kaplan-Meier survival curves. RESULTS: Over a median 13.92 (interquartile range 7.58-21.67) years of follow-up, patients with AS had a greater VF prevalence and greater incidence of developing a new VF compared to controls (9.3% vs 2.5%, 6.8% vs 1.9%, respectively, all P < 0.001). Patients with AS had an increased risk of developing a VF after adjustments for age, sex, and osteoporosis (HR 2.55, 95% CI 2.11-3.09) compared to controls; this risk remained throughout the study period. Patients with AS were 5 years younger at time of first VF (P = 0.008) and had a greater likelihood of a recurrent VF (IRR 4.64; 95% CI 4.54-4.75) compared to respective controls. Mortality overall was comparable between patients with AS and controls after adjustment for age, sex, osteoporosis, and VF status (HR 0.90; 95% CI 0.80-1.01). CONCLUSION: The significantly increased risk of VF in patients with AS has not altered following the introduction of tumor necrosis factor inhibitor treatment. Although patients with AS experience a first VF at a younger age than controls, this does not lead to an increased risk of death.

Infection Rates Before and After Diagnosis of IgA Vasculitis in Childhood: A Population-wide Study Using Non-exposed Matched Controls.

OBJECTIVE: Clinical data suggest that infections can trigger IgA vasculitis (IgAV), but longterm observations are lacking. We compared rates, types, and microorganisms for serious infection before and after diagnosis for children with IgAV and non-exposed controls. METHODS: Using population-based administrative linked health datasets we estimated incidence rates (IR) for serious infection per 1000 person-months for patients with IgAV (n = 504, age 5 yrs, 59.1% males) and controls matched for age, sex, and year of presentation (n = 1281, age 6 yrs, 66% males). Time zero (T0) was the date of IgAV diagnosis or equivalent date in controls, lookback (median 38 mos) was the period prior to T0, and followup (median 239 mos) was the period after T0. RESULTS: During lookback, prevalence of serious infection was similar in patients with IgAV and controls (11.5% vs 9.5%, respectively), but patients with IgAV had a higher rate of upper respiratory tract infections [incidence rate ratio (IRR) 1.79; 95% CI 1.39-2.31] with shorter time between first serious infection and T0 (27 vs 43 mos; p = 0.02). During followup, patients were at a constant increased risk for serious infections (IRR 1.46, 95% CI 1.35-1.58). These rates were higher during followup: sepsis (IRR 12.6), pneumonia (IRR 6.19), upper respiratory tract infections (IRR 2.36), and skin infections (IRR 1.85). There was little overlap between patients with serious infections in the lookback and followup periods. CONCLUSION: In patients with childhood IgAV there is an increased longterm risk for a broader spectrum of infections, which is unrelated to serious infections prior to diagnosis or treatment. This suggests disease-specific factors may have a lasting effect on immune competence in childhood IgAV.

IL-1A gene variation in relation to cytokine levels and clinical characteristics in ankylosing spondylitis.

OBJECTIVE: Variations in the IL-1 alpha (IL-A) gene increase the risk for ankylosing spondylitis (AS), but the pathway underlying this association is not fully understood. As IL-1A is primarily a regulatory cytokine, we investigated the influence of IL-1A gene variation on disease severity and cytokine expression in AS. METHODS: This was a cross sectional study of tumor necrosis factor inhibitors (TNFi)-naïve AS patients (n=334, 90% B27 +, age 45 years) fulfilling the modified New York criteria. We recorded demographics, clinical findings, spinal mobility, Bath AS Functional Index (BASFI), and routine lab findings. IL-1A genotyping for three AS-associated single nucleotide polymorphism (SNP; rs2856836, rs17561 and rs1894399) was performed using Taqman RT-PCR, with TNF, IL-6, IL-17A, and IL-23 levels measured using ELISA. Genotypic associations included logistic regression analysis for genotype (codominant model) and global haplotype (threshold 5%) associations with cytokine levels and clinical features. RESULTS: The three variants were in near complete linkage disequilibrium and formed two only common haplotypes (ACC 67%, GAT 33%). The levels for TNF, IL-6, IL-17A, IL-23, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were similar across genotypes and haplotypes (all p-values >0.4) as were the measures for spinal mobility and BASFI. The TAQ haplotype showed a borderline significant trend with reduced heart disease and mortality during follow-up. CONCLUSION: IL-1A gene cluster variations do not have an impact on the clinical disease measures or cytokine levels in AS, suggesting that IL-1A has no direct role in AS.

Disease Activity and Patient-Reported Health Measures in Relation to Cytokine Levels in Ankylosing Spondylitis.

INTRODUCTION: Ankylosing spondylitis (AS) is a lifelong condition where spinal inflammation causes chronic back pain and restriction of spinal function. While proinflammatory cytokines participate in the disease process, their relation with disease activity, spinal function, and quality of life is less well understood. METHODS: Cross-sectional study of serum levels of four inflammatory cytokines (IL-6, TNF, IL-23, and IL-17A) in AS patients not on biologics. Disease characteristics and simultaneous spinal function tests and patient-reported health measures (Bath Functional Index (BASFI), Dougados Functional Index (DFI), Modified Health Assessment Questionnaire (MHAQ), and routine laboratory parameters were recorded. The composite ASDAS-CRP score was used to classify disease activity as absent, low, or high. RESULTS: In 164 AS patients (age 46 years, 70.1% males, 90.9% HLAB27 positive, ASDAS-CRP 1.8), disease activity was classified as inactive in 14%, low in 54%, and high in 31%. ASDAS-CRP correlated well with MHAQ, DFI, BASFI, and spinal mobility across patients with low and high disease activity (all p < 0.05). Cytokine levels did not correlate with ASDAS-CRP, ESR, BASFI, or spinal mobility scores and were comparable between patients with no, low, or high disease activity regardless of gender or disease duration (all p > 0.2). CONCLUSIONS: A large proportion of AS not on biologics have active disease far into the disease course. This impacts negatively on quality of life, work ability, and spinal mobility. Serum cytokine levels are poor markers for these central disease features in AS management. FUNDING: Abbott Norway AS and Arthritis Foundation of Western Australia.

Sporadic late onset nemaline myopathy (SLONM) in an adult presenting with progressive muscle weakness.

Sporadic late onset nemaline myopathy (SLONM) is a rare, intractable acquired myopathy that is characterised by progressive muscle weakness and the presence of nemaline rods in myofibres. Unlike the congenital form of nemaline myopathy (NM), there are only few case reports and series on SLONM in the scientific literature. We present a case report of SLONM in a 62-year-old male from a rural town in Western Australia, without any of the conditions often associated with SLONM such as monoclonal gammopathy of uncertain significance or HIV infection. SLONM should be considered in the differential diagnosis of progressive proximal muscle weakness in an adult.

IL23R gene variants in relation to IL17A levels and clinical phenotype in patients with ankylosing spondylitis.

BACKGROUND: IL23 receptor (IL23R) binding by IL23 is required for the maturation of CD4+ cells into Th17 cells and subsequent generation of IL17A and TNF. As IL23R variations contribute to AS susceptibility, we investigated the effect of IL23R variants on cytokine levels and disease measures in an AS cohort. METHODS: This was a cross-sectional study of AS patients (n = 334, 90% B27+, age 45 years). IL23R genotyping for three non-synonymous single-nucleotide polymorphisms (rs11209026, protective allele A; rs10489629, protective allele A; and rs11209032, risk allele A) was done by Taqman RT-PCR. IL23, IL17A, TNF and IL6 concentrations were determined by sandwich ELISA. Genotypic associations were analysed with non-parametric methods. RESULTS: Twenty-two AS patients (6.6%) carried the protective rs11209026 A allele, whereas 206 (61.7%) carried the rs11209032A risk allele (P = 0.03). Two patients homozygous for rs11209026A had late onset, no co-morbidity and undetectable cytokine levels. IL23R genotypes and five common haplotypes were unrelated with age at onset, BASFI or co-morbidity (all P >0.2). There was no overall difference in the concentration of IL17A (184 vs 233 pg/ml, P > 0.2) or IL23 (276 vs 262 pg/ml, P > 0.4) between AS patients and controls, but a global haplotype association (P = 0.01) was observed for IL23 concentrations. CONCLUSION: Homozygosity for rs11209026A is rare in AS patients, but may ameliorate the clinical presentation. IL17A and IL23 levels are similar in controls and AS patients. IL23R variants influence IL23 levels but not IL17A levels in AS patients, suggesting that IL23R impacts more on cell types other than Th17 cells.

Recurrent podocytopathy in a patient with systemic lupus erythematosus.

Podocytopathy in systemic lupus erythematosus is characterised by diffuse foot process effacement without significant peripheral capillary wall immune deposits as seen on electron microscopy. Lupus podocytopathy falls outside the scope of the current International Society of Nephrology and the Renal Pathology Society classification of lupus nephritis. We present a case of relapsing podocytopathy with nephrotic syndrome occurring simultaneously with two extra-renal and serological disease flares, which makes it likely that podocytopathy was related to systemic lupus erythematosus activity. This case adds to the growing body of evidence that lupus podocytopathy must be considered in the differential diagnosis of systemic lupus erythematosus patients presenting with nephrotic syndrome.

Risk of mortality in patients with giant cell arteritis: A systematic review and meta-analysis.

BACKGROUND: Previous studies of mortality associated with GCA have shown conflicting results. We conducted a systematic review and meta-analysis to determine the mortality risk in GCA patients compared to the general population. METHODS: We searched for published studies indexed in MEDLINE and EMBASE and the Cochrane database from inception to June 18, 2015 using the terms "giant cell arteritis" and "temporal arteritis" combined with the terms for death, mortality, and survival. A manual search of citations from retrieved articles was also performed. The inclusion criteria were as follows: (1) observational studies of mortality in GCA and (2) comparison of mortality to the general population. Studies published only in abstract form were excluded. Study eligibility and quality (Newcastle-Ottawa scale) were independently assessed by at least two investigators. Random effects meta-analysis of the mortality ratio (MR) was performed by the inverse variance method. RESULTS: Out of 435 potentially relevant articles, 64 studies were reviewed, 19 studies were included in the review and 17 studies were included in the meta-analysis. Mortality was not increased in GCA patients ascertained from a population base (MR = 1.03, 95% CI: 0.96-1.10), but was increased in patients ascertained from a hospital setting (MR = 1.61, 95% CI: 1.19-2.19). There was no difference in MR by gender, and two studies provided evidence that mortality was increased in the early years following diagnosis. CONCLUSION: At a population level, long-term mortality is not increased in GCA. However, mortality risk may be increased in some patients, and may vary over time.

CD4 cell count and CD4/CD8 ratio increase during rituximab maintenance in granulomatosis with polyangiitis patients.

INTRODUCTION: Rituximab (RTX) is a B cell-depleting agent approved for the treatment of granulomatosis with polyangiitis (GPA). RTX reduces antibody producing precursor plasma cells and inhibits B and T cells interaction. Infections related to T cell immunodeficiency are not infrequent during RTX treatment. Our study investigated CD4 cell count and CD4/CD8 ratio in GPA patients during the first two years of long-term RTX treatment. METHODS: A single centre cohort study of 35 patients who received median total cumulative dose of cyclophosphamide (CYC) of 15 g and were treated with RTX 2 g followed by retreatment with either 2 g once annually or 1 g biannually. Serum levels of total immunoglobulin (Ig) and lymphocytes subsets were recorded at RTX initiation and at 3, 6, 12, 18 and 24 months. Low CD4 count and inverted CD4/CD8 ratio were defined as CD4 < 0.3 × 10(9)/l and ratio < 1. RESULTS: The CD4 cell count and CD4/CD8 ratio decreased slightly following the initial RTX treatment and then increased gradually during maintenance treatment. While the proportion of patients with low CD4 cell count decreased from 43% at baseline to 18% at 24 months, the ratio remained inverted in 40%. Oral daily prednisolone dose at baseline, CYC exposure and the maintenance regimen did not influence the CD4 cell count and ratio. Being older (p = 0.012) and having a higher CRP (p = 0.044) and ESR (p = 0.024) at baseline significantly increased the risk of inverted CD4/CD8 ratio at 24 months. Inverted ratio at baseline associated with lower total Ig levels during the study. CONCLUSIONS: Overall, the CD4 and CD4/CD8 ratio increased during maintenance RTX therapy in GPA with no discernible impact of other immunosuppressive therapy. However the increase in CD4 was not followed by an increase in the CD4/CD8 ratio, especially in older patients. Inverted CD4/CD8 ratio associated with lower Ig levels, suggesting a more profound B cell depleting effect of RTX with a relative increase in CD8+ lymphocytes.