The development and evaluation of dose-prediction tools for allopurinol therapy (Easy-Allo tools).

AIMS: Dose escalation at the initiation of allopurinol therapy can be protracted and resource intensive. Tools to predict the allopurinol doses required to achieve target serum urate concentrations would facilitate the implementation of more efficient dose-escalation strategies. The aim of this research was to develop and externally evaluate allopurinol dosing tools, one for use when the pre-urate-lowering therapy serum urate is known (Easy-Allo1) and one for when it is not known (Easy-Allo2). METHODS: A revised population pharmacokinetic-pharmacodynamic model was developed using data from 653 people with gout. Maintenance doses to achieve the serum urate target of <0.36 mmol L-1 in >80% of individuals were simulated and evaluated against external data. The predicted and observed allopurinol doses were compared using the mean prediction error (MPE) and root mean square error (RMSE). The proportion of Easy-Allo predicted doses within 100 mg of the observed was quantified. RESULTS: Allopurinol doses were predicted by total body weight, baseline urate, ethnicity and creatinine clearance. Easy-Allo1 produced unbiased and suitably precise dose predictions (MPE 2 mg day-1 95% confidence interval [CI] -13-17, RMSE 91%, 90% within 100 mg of the observed dose). Easy-Allo2 was positively biased by about 70 mg day-1 and slightly less precise (MPE 70 mg day-1 95% CI 52-88, RMSE 131%, 71% within 100 mg of the observed dose). CONCLUSIONS: The Easy-Allo tools provide a guide to the allopurinol maintenance dose requirement to achieve the serum urate target of <0.36 mmol L-1 and will aid in the development of novel dose-escalation strategies for allopurinol therapy.

Rheumatoid interstitial lung disease in Canterbury, Aotearoa New Zealand - A retrospective cohort study.

BACKGROUND: Rheumatoid arthritis associated interstitial lung disease (RA-ILD), is an important extra-articular manifestation of rheumatoid arthritis (RA). The frequency, risk factors, and prognosis of RA-ILD are incompletely understood. AIMS: To determine the prevalence and incidence, clinical characteristics and risk factors for development, and outcomes of persons with RA-ILD in the population of the Canterbury District Health Board (CDHB) catchment area. METHODS: Individuals aged ≥ 18 years with RA, resident in the CDHB catchment area between 1 January 2006 and 31 December 2008 (Period One), and 1 January 2011 to 31 December 2013 (Period Two) were identified by medical record review and followed until 30 June 2019. Individuals with RA-ILD as defined by pre-specified criteria were identified. The association between demographic and clinical characteristics and RA-ILD development and mortality was examined using Cox-proportional hazards models. RESULTS: The prevalence of RA-ILD per 100,000 was 10.97 (95 % CI 7.53,14.42) for Period One, and 14.74 (95 % CI 10.84,18.63) for Period Two. Among individuals evaluated for risk factors for RA-ILD development, the estimated cumulative incidence of ILD at 10 years was 4.47 % (95 % CI 3.14, 6.14). After adjusting for age, rheumatoid factor positivity (HR 3.73, 95 % CI, 1.32,10.56), extra-articular manifestations other than RA-ILD (HR 4.48, 95 % CI 2.36,8.48), and subcutaneous rheumatoid nodules (HR 4.66, 95 % CI 2.34, 9.26) were associated with increased risk of developing RA-ILD. The standardised mortality ratio for RA-ILD was 3.90 (95 % CI 2.55,5.72) compared to the general population. Extent of ILD on CT chest was associated with mortality (HR for >20% vs. < 20 % 4.47, 95 % CI 1.67,11.96). CONCLUSIONS: Clinically evident RA-ILD occurred in approximately 5 % of individuals with RA. Mortality was increased almost fourfold compared to the general population. Radiologic extent was the most important prognostic factor.

Is colchicine prophylaxis required with start-low go-slow allopurinol dose escalation in gout? A non-inferiority randomised double-blind placebo-controlled trial.

OBJECTIVES: To determine whether placebo is non-inferior to low-dose colchicine for reducing gout flares during the first 6 months of allopurinol using the 'start-low go-slow' dose approach. METHODS: A 12-month double-blind, placebo-controlled non-inferiority trial was undertaken. Adults with at least one gout flare in the preceding 6 months, fulfilling the American College of Rheumatology (ACR) recommendations for starting urate-lowering therapy and serum urate ≥0.36 mmol/L were recruited. Participants were randomised 1:1 to colchicine 0.5 mg daily or placebo for the first 6 months. All participants commenced allopurinol, increasing monthly to achieve target urate <0.36 mmol/L. The primary efficacy outcome was the mean number of gout flares/month between 0 and 6 months, with a prespecified non-inferiority margin of 0.12 gout flares/month. The primary safety outcome was adverse events over the first 6 months. RESULTS: Two hundred participants were randomised. The mean (95% CI) number of gout flares/month between baseline and month 6 was 0.61 (0.47 to 0.74) in the placebo group compared with 0.35 (0.22 to 0.49) in the colchicine group, mean difference 0.25 (0.07 to 0.44), non-inferiority p=0.92. There was no difference in the mean number of gout flares/month between randomised groups over the 12-month period (p=0.68). There were 11 serious adverse events in 7 participants receiving colchicine and 3 in 2 receiving placebo. CONCLUSIONS: Placebo is not non-inferior to colchicine in prevention of gout flares in the first 6 months of starting allopurinol using the 'start-low go-slow' strategy. After stopping colchicine, gout flares rise with no difference in the mean number of gout flares/month between groups over a 12-month period. TRIAL REGISTRATION NUMBER: ACTRN 12618001179224.

The 2023 ACR/EULAR Classification Criteria for Calcium Pyrophosphate Deposition Disease.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score >56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

The 2023 ACR/EULAR classification criteria for calcium pyrophosphate deposition disease.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

Long-Term Follow-up of a Randomized Controlled Trial of Allopurinol Dose Escalation to Achieve Target Serum Urate in People With Gout.

OBJECTIVE: To determine the long-term use of and adherence to urate-lowering therapy (ULT), serum urate (SU) control, and self-reported flares in participants from a randomized controlled trial of allopurinol dose escalation, in order to achieve target SU concentration (< 0.36 mmol/L) in people with gout. METHODS: For surviving study participants, ULT dispensing and SU testing within the preceding 12 months was obtained by medical record review. A phone interview was conducted to determine self-reported flares and adherence. RESULTS: Over a mean follow-up of 6.5 (SD 2.5) years since enrollment, 60 out of 183 (33%) participants had died. Review of the 119 surviving participants showed that 98 (82%) were receiving allopurinol, 5 (4%) were receiving febuxostat, and 10 (8%) were not receiving ULT; for the remaining 6 (5.0%), ULT use could not be determined. In those receiving allopurinol, the mean dose was 28.1 (range -600 to 500) mg/day lower than at the last study visit; 49% were receiving the same dose, 18% were on a higher dose, and 33% were on a lower dose than at the last study visit. SU values were available for 86 of the 119 (72%) participants; 50 out of 86 (58%) participants had an SU concentration of < 0.36 mmol/L. Of the 89 participants who participated in the phone interview, 19 (21%) reported a gout flare in the preceding 12 months and 79 (89%) were receiving allopurinol; 71 (90%) of those receiving allopurinol reported 90% or greater adherence. CONCLUSION: Most of the surviving participants in the allopurinol dose escalation study had good real-world persistence with allopurinol, remained at target SU, and had a low number of self-reported flares.

Rates of Joint Replacement Surgery in New Zealand, 1999-2015: A Comparison of Rheumatoid Arthritis and Osteoarthritis.

OBJECTIVE: To determine rates of joint replacement for people with rheumatoid arthritis (RA) and osteoarthritis (OA) and to examine the characteristics of those receiving elbow replacements. METHODS: Data were extracted from the New Zealand Joint Registry from 1999 to 2015 and annual rates calculated. RESULTS: Rates of joint replacement increased over time for OA but not RA. Elbow replacement was the only procedure performed more commonly in RA. CONCLUSION: There has been a substantial increase in joint replacement for OA in New Zealand. For RA, where access to biologics has been limited to those with erosions, joint replacement rates have not declined, with the exception of elbow replacements.