Optimising patient outcomes: temporal trends in remission rates of rheumatoid arthritis patients in the Australian OPAL dataset between 2009 and 2022.

OBJECTIVE: To describe the trends in remission rates among RA patients in the OPAL dataset, spanning from 2009 to 2022, and provide insights into the effectiveness of evolving RA management approaches in real-world clinical settings. METHODS: Patients with a physician diagnosis of RA and at least 3 visits between 1 January 2009 and December 2022 were identified in the OPAL dataset, an aggregated collection of data extracted from the electronic medical records of patients managed by 117 Australian rheumatologists. Demographics, disease history, prescribed medications and proportions of patients in Disease Activity Score 28-joint count C-reactive protein (DAS28CRP)) categories (remission, low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA)) were described. RESULTS: A large population (n = 48,388) of eligible patients with RA were identified in the OPAL dataset. A consistent and substantial improvement in DAS28CRP remission rates were found in (i) all patients, (ii) patients managed on conventional synthetic disease-modifying antirheumatic drugs (csDMARD) and (iii) patients treated with biological or targeted synthetic (b/ts)DMARD therapy, increasing from approximately 50% in 2009 to over 70% by 2022. The increase in DAS28CRP remission was accompanied by reduced proportions of patients in MDA and HDA states. CONCLUSION: This study highlights a consistent improvement in disease activity and rising remission rates among Australian RA patients within the OPAL dataset, offering the potential for enhanced patient outcomes and reduced disease burden.

Real-world evaluation of persistence, effectiveness and usage patterns of tofacitinib in treatment of psoriatic arthritis in Australia.

OBJECTIVES: To describe treatment patterns and persistence of tofacitinib, interleukin 17 inhibitors (IL-17Ai) and tumour necrosis factor inhibitors (TNFi), in patients with psoriatic arthritis (PsA). METHODS: Data from adult patients with PsA and who had received at least one prescription of tofacitinib, IL-17Ai or TNFi between May 2019 and September 2021 were sourced from the Australian OPAL dataset. Persistence, analysed via Kaplan-Meier methods, and propensity score matching between tofacitinib and bDMARD (IL-17Ai and TNFi) groups were conducted. RESULTS: Of 16,692 patients with PsA, 1486 (n = 406 tofacitinib, n = 416 IL-17Ai and n = 664 TNFi) were included. More females were in the tofacitinib group (75.4%) than in the IL-17Ai (61.1%) and TNFi (64.8%) groups. Overall, 19.2% of tofacitinib patients were first line, compared with 41.8% of IL-17Ai and 62.8% of TNFi patients. In the overall population, the median persistence was 16.5 months (95% CI 13.8 to 19.5 months), 17.7 months (95% CI 15.8 to 19.6 months) and 17.2 months (95% CI 14.9 to 20.5 months) in the tofacitinib, IL-17Ai and TNFi groups, respectively. Persistence was similar in the tofacitinib/IL-17Ai matched population; however, in the tofacitinib/TNFi matched population, persistence was longer in the tofacitinib group (18.7 months, 95% CI 15.6 to 21.4 months) compared with the TNFi group (12.2 months, 95% CI 19.9 to 14.9 months). CONCLUSIONS: In this Australian real-world dataset, tofacitinib was more frequently used in later lines and among a slightly higher proportion of female patients than IL-17Ai or TNFi. Overall, treatment persistence was similar for tofacitinib, IL-17Ai and TNFi, but tofacitinib exhibited longer persistence than TNFi in a matched population. Key Points • This is the first, large real-world study from Australia investigating the demographics, treatment patterns and comparative treatment persistence of patients with psoriatic arthritis (PsA) treated with tofacitinib and biologic disease-modifying drugs (bDMARDs). • The study suggests that tofacitinib is an effective intervention in PsA with at least comparable persistence to bDMARDs: tumour necrosis factor inhibitors (TNFi) and interleukin-17 A inhibitors (IL-17Ai).

Comparative effectiveness of etanercept originator and biosimilar for treating rheumatoid arthritis: implications for cost-savings.

BACKGROUND AND AIMS: This study aimed to assess the comparative effectiveness of the etanercept (ETN) originator (Enbrel) and ETN biosimilar SB4 (Brenzys) as first-line treatment in patients with rheumatoid arthritis (RA), while also exploring the potential cost-savings associated with this approach in Australia. METHODS: Clinical data were obtained from the Optimising Patient outcomes in rheumatoLogy Australian real-world data set. Adult patients with RA who had initiated treatment with the ETN originator or biosimilar as their first-recorded biologic or targeted synthetic disease-modifying antirheumatic drug between 1 April 2017 and 31 December 2020 were included. Treatment persistence was analysed using survival analysis. Cost-savings were estimated based on data reported by the Australian National Prescribing Service MedicineWise. RESULTS: Propensity score matching followed by inverse probability of treatment weighting selected patients taking originator (n = 209) or biosimilar (n = 141) with similar baseline characteristics and eliminated small differences in baseline disease activity. The median time for 50% of the patients to stop treatment was 19.4 months (95% confidence interval [CI], 14.7-36.4 months) for the originator and 22.4 months (95% CI, 15.0-33.1 months) for the biosimilar (P = 0.95). As a result of pricing policies established by the Australian Government, introduction of the ETN biosimilar would have resulted in a cost-savings of over AU$9.5 million for 1 year of treatment for the patients reported in this study. CONCLUSION: Treatment persistence using either ETN originator or biosimilar was similar. The cost of all brands of ETN markedly reduced upon listing of the ETN biosimilar, resulting in significant savings for the Australian Government.

Burden of disease and real-world treatment patterns of patients with systemic lupus erythematosus in the Australian OPAL dataset.

OBJECTIVE: To describe the demographics, disease burden and real-world management of patients with systemic lupus erythematosus (SLE) in Australian community practice. METHODS: Patients with a physician diagnosis of SLE and at least 1 visit between 1 January 2009 and 31 March 2021 were identified in the OPAL dataset, an aggregated collection of data extracted from the electronic medical records of patients managed by 112 Australian rheumatologists. Demographics, basic clinical features and prescribed medications were described, with medication combinations used as a surrogate of disease severity. RESULTS: Of 5133 patients with a diagnosis of lupus, 4260 (83%) had SLE. Of these SLE patients, almost 90% of patients were female, with a median age of 49 years [IQR 37-61] at first-recorded visit. Of the 2285 SLE patients whose most recent visit was between 1 January 2019 and 31 March 2021, 52.5% had mild disease, 29.9% had moderate-severe disease and 7.4% had very severe disease. Visit frequency increased with disease severity. Most patients (85.8%) were treated with hydroxychloroquine, typically prescribed as first line-of-therapy. CONCLUSION: In this large real-world Australian cohort of patients with SLE, a substantial burden of disease was identified, with a significant proportion (almost one-third of patients) considered to have moderate to severe disease based on medication use. This study provides a greater understanding of the path from symptom onset to treatment and the heterogeneous presentation of patients with SLE who are treated in community practice in Australia. Key messages • Most published studies describing patients with SLE are derived from specialist lupus centres, typically in the hospital setting, therefore little is known about the characteristics of patients with SLE who are receiving routine care in community clinics. • The OPAL dataset is a large collection of clinical data from the electronic medical records of rheumatologists predominantly practising in private community clinics, which is where the majority (73-80%) of adult rheumatology services are conducted in Australia [1-3] . Since data from community care has not been widely available for SLE research, this study contributes important insight into this large and under-reported patient population. • To improve access to care and effective treatments, and reduce the burden of SLE in Australia, a greater understanding of the characteristics and unmet needs of patients with SLE managed in the community setting is required.

Comparative Effectiveness of Adalimumab vs Tofacitinib in Patients With Rheumatoid Arthritis in Australia.

Importance: There is a need for observational studies to supplement evidence from clinical trials, and the target trial emulation (TTE) framework can help avoid biases that can be introduced when treatments are compared crudely using observational data by applying design principles for randomized clinical trials. Adalimumab (ADA) and tofacitinib (TOF) were shown to be equivalent in patients with rheumatoid arthritis (RA) in a randomized clinical trial, but to our knowledge, these drugs have not been compared head-to-head using routinely collected clinical data and the TTE framework. Objective: To emulate a randomized clinical trial comparing ADA vs TOF in patients with RA who were new users of a biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD). Design, Setting, and Participants: This comparative effectiveness study emulating a randomized clinical trial of ADA vs TOF included Australian adults aged 18 years or older with RA in the Optimising Patient Outcomes in Australian Rheumatology (OPAL) data set. Patients were included if they initiated ADA or TOF between October 1, 2015, and April 1, 2021; were new b/tsDMARD users; and had at least 1 component of the disease activity score in 28 joints using C-reactive protein (DAS28-CRP) recorded at baseline or during follow-up. Intervention: Treatment with either ADA (40 mg every 14 days) or TOF (10 mg daily). Main Outcomes and Measures: The main outcome was the estimated average treatment effect, defined as the difference in mean DAS28-CRP among patients receiving TOF compared with those receiving ADA at 3 and 9 months after initiating treatment. Missing DAS28-CRP data were multiply imputed. Stable balancing weights were used to account for nonrandomized treatment assignment. Results: A total of 842 patients were identified, including 569 treated with ADA (387 [68.0%] female; median age, 56 years [IQR, 47-66 years]) and 273 treated with TOF (201 [73.6%] female; median age, 59 years [IQR, 51-68 years]). After applying stable balancing weights, mean DAS28-CRP in the ADA group was 5.3 (95% CI, 5.2-5.4) at baseline, 2.6 (95% CI, 2.5-2.7) at 3 months, and 2.3 (95% CI, 2.2-2.4) at 9 months; in the TOF group, it was 5.3 (95% CI, 5.2-5.4) at baseline, 2.4 (95% CI, 2.2-2.5) at 3 months, and 2.3 (95% CI, 2.1-2.4) at 9 months. The estimated average treatment effect was -0.2 (95% CI, -0.4 to -0.03; P = .02) at 3 months and -0.03 (95% CI, -0.2 to 0.1; P = .60) at 9 months. Conclusions and Relevance: In this study, there was a modest but statistically significant reduction in DAS28-CRP at 3 months for patients receiving TOF compared with those receiving ADA and no difference between treatment groups at 9 months. Three months of treatment with either drug led to clinically relevant average reductions in mean DAS28-CRP, consistent with remission.

Comparative Effectiveness of First-Line Baricitinib in Patients With Rheumatoid Arthritis in the Australian OPAL Data Set.

OBJECTIVE: To analyze comparative treatment persistence for first-line baricitinib (BARI) versus first-line tumor necrosis factor inhibitor (TNFi) in patients with rheumatoid arthritis (RA) and for first-line BARI initiated as monotherapy versus first-line BARI initiated with at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD). METHODS: Patients with RA who initiated BARI or TNFi as first-line biologic or targeted synthetic DMARD from October 1, 2015, to September 30, 2021, were identified in the OPAL data set. Drug survival times to 6, 12, and 24 months were analyzed using restricted mean survival time (RMST). Multiple imputation and inverse probability of treatment weighting were used to address missing data and nonrandom treatment assignment. RESULTS: A total of 545 patients initiated first-line BARI, including 118 as monotherapy and 427 as csDMARD combination therapy. Three thousand five hundred patients initiated first-line TNFi. There was no difference in drug survival to 6 or 12 months for BARI compared with TNFi; differences in RMST were 0.02 months (95% CI: -0.08 to 0.013; P = 0.65) and 0.31 months (95% CI: -0.02 to 0.63; P = 0.06), respectively. Patients in the BARI group had 1.00 month (95% CI: 0.14 to 1.86; P = 0.02) longer drug survival to 24 months. There was no difference in drug survival for BARI monotherapy compared with combination therapy, with differences in RMST to 6, 12, and 24 months of -0.19 months (95% CI: -0.50 to 0.12; P = 0.12), -0.35 months (95% CI: -1.17 to 0.42; P = 0.41), and -0.56 months (95% CI: -2.66 to 1.54; P = 0.60), respectively. CONCLUSION: In this comparative analysis, treatment persistence up to 24 months was significantly longer for first-line BARI compared with TNFi, but the effect size of 1.00 month is not clinically meaningful. There was no difference in persistence for BARI monotherapy versus combination therapy.

A novel electronic patient-reported outcome delivery system to implement health-related quality of life measures in routine clinical care: An analysis of 5 years of experience.

Objective: To develop a simple and secure technological solution to incorporate electronic patient-reported outcomes (ePROs) into routine clinical care. Methods: A novel ePRO questionnaire delivery system was developed by Software for Specialists (S4S) in partnership with OPAL Rheumatology Australia. Validated questionnaires were sent from the electronic medical record (EMR) (Audit4) of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), lupus or giant cell arteritis (GCA) and delivered to the patient's email address or completed in the clinic waiting room using a smart device (in-practice). Completed questionnaires were encrypted and returned to the patient's Audit4. Deidentified clinical data was extracted and aggregated across all sites. Data collected between April 2016-Dec 2020 were analysed descriptively. Results: Between April 2016 to Dec 2020, 221,352 Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F), Patient Health Questionnaire-2 (PHQ-2) and/or HealthCare Resource Utilization (HCRU) questionnaires were sent from 39 of 42 contributing clinics (93%). 85% of questionnaires were delivered via email and 15% in-practice. Overall, 85% of patients completed at least one questionnaire, and of all questionnaires sent, 73% were completed. Females were more likely to engage with the questionnaires than males (87% vs. 81%), and older patients were slightly more likely to complete all questionnaires delivered. Conclusions: The novel Audit4 ePRO delivery system is an effective tool for incorporating PROs into routine clinical care. The data generated provides a unique opportunity to understand the full burden of disease for patients in the real-world setting and the impact of interventions.

Prevalence of sleep disturbance and the association between poor disease control in people with ankylosing spondylitis within the Australian clinical setting (ASLEEP study): a real-world observational study using the OPAL dataset.

INTRODUCTION: Sleep disturbance and fatigue are commonly reported in ankylosing spondylitis (AS) but specific prevalence and the relationship to disease control are unknown. METHOD: This retrospective non-interventional observational study of data from the OPAL dataset included patients with AS (ICD code M45, M45.0 or M08.1), aged 18 to 95 years and had completed ≥ 1 sleep questionnaire between 1 January 2019 and 30 September 2020. The prevalence of insomnia and obstructive sleep apnoea were assessed using the Insomnia Severity Index (ISI) and Multivariate Apnoea Prediction Index (MAPI), respectively. Propensity score (PS) matching based on sex, age and symptom duration increased comparability between patients administered tumour necrosis factor inhibitors (TNFi) and interleukin 17A inhibitors (IL-17Ai). RESULTS: Four hundred ninety-five patients were included. The mean ISI total score in the overall population was 8.6 ± 6.2. Self-reported moderate or severe clinical insomnia was present in 16% and 3.2% of patients, respectively. The mean MAPI score was 0.4 ± 0.3, self-reported apnoea was identified in 31.5% of patients and the mean FACIT-Fatigue score was 36.1 ± 10.7. In the PS matched population, the only treatment-related difference was the mean MAPI score (IL-17Ai 0.4 ± 0.3 and TNFi 0.3 ± 0.2, p = 0.046). Those with poor disease control (BASDAI ≥ 4) were more likely (odds ratio [OR] 7.29, 95% CI 2.37 to 22.46, p = 0.001) to have a greater severity of insomnia symptoms than those with good disease control. CONCLUSION: In this real-world AS cohort, poor disease control was associated with sleep disturbance. Little difference in sleep disturbance was observed between biologic TNFi and IL-17Ai treatment. Key Points • Sleep disturbance and fatigue are common in patients with ankylosing spondylitis. • In our real-world cohort, self-reported apnoea was reported in one-third of patients; and one in five patients reported moderate to severe insomnia. • Those with poor disease control were more likely to experience greater sleep disturbance than those with good disease control.

Persistence to Biologic Therapy Among Patients With Ankylosing Spondylitis: An Observational Study Using the OPAL Dataset.

OBJECTIVE: To describe the treatment response and persistence to biologic disease-modifying antirheumatic drug (bDMARD) therapy in patients with ankylosing spondylitis (AS) in a real-world Australian cohort. METHODS: This was a retrospective, noninterventional cohort study that extracted data for patients with AS from the Optimising Patient outcomes in Australian RheumatoLogy (OPAL) dataset for the period of August 2006 to September 2019. Patients were classified as either bDMARD initiators if they commenced a bDMARD during the sampling window, or bDMARD-naïve if they did not. Results were summarized descriptively. Treatment persistence was calculated using Kaplan-Meier methods. Differences in treatment persistence were explored using log-rank tests. RESULTS: There were 5048 patients with AS identified. Of these, 2597 patients initiated bDMARDs and 2451 remained bDMARD-naïve throughout the study window. Treatment with first-, second-, and third-line bDMARDs significantly reduced disease activity. Median persistence on first-line bDMARDs was 96 months (95% CI 85-109), declining to 19 months (95% CI 16-22) in second-line therapy, and 15 months (95% CI 11-18) in third-line therapy. Median persistence was longest for the golimumab (GOL) group in all lines of therapy and shortest for the etanercept (ETN) group. Differences in persistence rates according to the time period that bDMARDs were prescribed (pre- and post-2012) were also seen for ETN and adalimumab. CONCLUSION: In this cohort, all bDMARDs effectively reduced AS disease activity. Treatment persistence was sustained for up to 8 years for patients remaining on their first bDMARD, longer than on subsequent agents. Further research is needed to determine its influence on treatment recommendations.

Real-world evaluation of effectiveness, persistence, and usage patterns of monotherapy and combination therapy tofacitinib in treatment of rheumatoid arthritis in Australia.

OBJECTIVE: This study aimed to describe the real-world effectiveness and treatment persistence among patients with rheumatoid arthritis treated with monotherapy and combination therapy tofacitinib and biologic disease-modifying antirheumatic drugs (bDMARDs). METHODS: This was a post hoc analysis of a retrospective, non-interventional study that extracted data for patients treated with tofacitinib or bDMARDs from the Australian OPAL dataset between March 2015 and September 2018. Monotherapy tofacitinib and bDMARDs and combination therapy tofactinib and bDMARDs were propensity score matched and treatment effectiveness and persistence of the groups were evaluated. RESULTS: In the bDMARD and tofacitinib monotherapy and combination therapy matched populations there were 1300 bDMARD initiators (n = 564 monotherapy) and 650 tofacitinib initiators (n = 282 monotherapy). In the bDMARD and tofacitinib monotherapy matched groups, 62.9% and 66.7% were in DAS-28 CRP disease remission after 18 months of treatment, respectively. In the combination therapy bDMARD and tofacitinib groups, 50% and 58.9% were in DAS-28 CRP disease remission after 18 months, respectively. The median treatment persistence was similar between the monotherapy bDMARD and tofacitinib treatment groups (36.7 months (95% CI 27.4 to "not reached') and 34.2 months (95%CI 30.3 to "not reached") respectively) as well as the combination therapy bDMARD and tofacitinib groups (32.2 months (95% CI 25.7 to 34.4) and 32.7 months (95%CI 28.7 to "not reached", respectively). CONCLUSIONS: Patients receiving combination therapy with tofacitinib or bDMARDs had higher disease activity scores at index than patients receiving monotherapy. Monotherapy with tofacitinib or bDMARDs, and combination therapy with tofacitinib or bDMARDs demonstrated similar treatment effectiveness and persistence, respectively. Key Points • This study provides real-world evidence regarding effectiveness, treatment persistence, and treatment patterns, among patients with rheumatoid arthritis (RA) treated with monotherapy or combination therapy tofacitinib. • The study suggests that monotherapy and combination therapy tofacitinib is an effective intervention in RA with persistence and effectiveness comparable to bDMARDs.

Impact of anti-citrullinated protein antibody on tumor necrosis factor inhibitor or abatacept response in patients with rheumatoid arthritis.

OBJECTIVE: To assess the impact of anti-citrullinated protein antibody (ACPA) serostatus on response to treatment with either tumor necrosis factor inhibitors (TNFi) or abatacept in patients with rheumatoid arthritis (RA). METHODS: Data was obtained from the Optimizing Patient outcomes in Australian RheumatoLogy (OPAL) dataset. Patient data were included in the analysis if they commenced treatment with abatacept or TNFi between 01 August 2006 and 30 June 2017 and had at least 12 months' follow-up. The primary outcome was the mean change in the clinical disease activity index (CDAI) score from baseline to 12 months. RESULTS: A total of 2,052 patients were included of which 1,415 were in the TNFi cohort (n=1,053 ACPA positive) and 637 in the abatacept cohort (n=445 ACPA positive). Patients were predominantly female (75% TNFi; 80% abatacept) with no significant difference in age between cohorts. Patients with ACPA positivity had longer disease duration before commencing treatment in both the TNFi and abatacept cohorts compared to ACPA negative patients. No difference in disease severity was observed in those with ACPA negativity compared to those with ACPA positivity. Patients treated with TNFi and abatacept had significantly improved mean change in CDAI after 12 months; ACPA positivity was associated with greater response to treatment with abatacept compared to that in patients with ACPA negativity (p=0.011). No difference in response was observed based on ACPA serostatus in patients treated with TNFi (p=0.73). CONCLUSION: Baseline ACPA positivity was associated with improved clinical response using CDAI outcome measure at 12 months for abatacept but not for TNFi therapies.

Real-world evaluation of effectiveness, persistence, and usage patterns of tofacitinib in treatment of rheumatoid arthritis in Australia.

INTRODUCTION: The aim of this study was to describe the real-world evidence for effectiveness, treatment persistence, and treatment patterns among patients in the community with rheumatoid arthritis treated with the JAK inhibitor tofacitinib. METHODS: This was a retrospective, non-interventional cohort study that extracted data for new users of tofacitinib or biologic disease-modifying antirheumatic drugs (bDMARDs) from the Australian Optimizing Patient outcomes in Australian RheumatoLogy (OPAL) dataset between March 2015 and September 2018. Patients were propensity score matched at a 1:2 tofacitinib to bDMARD ratio based on age, sex, and selected baseline treatment combinations. Treatment effectiveness was evaluated using disease status measures. Treatment persistence was calculated and the percentage of patients receiving monotherapy or combination therapy at treatment initiation was evaluated. RESULTS: Data from 2810 patients were extracted and 1950 patients were included in the matched population (1300 bDMARD initiators and 650 tofacitinib initiators). Patients were predominantly aged 55 to 74 years (57.8%) and female (81.2%). After 18 months of treatment, 52.4% and 57.8% of patients had achieved disease activity score (DAS) remission in the bDMARD and tofacitinib groups, respectively. The median treatment persistence for tofacitinib was similar to that for bDMARDs: 34.2 months (95% CI 32.2 to not reached) and 33.8 months (95% CI 28.8 to 40.4), respectively. In the overall population, more patients were prescribed tofacitinib as monotherapy (43.4%) compared with bDMARD monotherapy (33.4%). CONCLUSIONS: Tofacitinib demonstrated treatment effectiveness and persistence similar to bDMARDs. Overall, there was a trend for more use of tofacitinib as monotherapy than bDMARDs. Key Points • This study provides real-world evidence regarding effectiveness, treatment persistence, and treatment patterns, among patients with rheumatoid arthritis (RA) in the community being treated with tofacitinib. • The study suggests that tofacitinib is an effective and enduring intervention in RA with tofacitinib persistence and effectiveness comparable to bDMARDs.

Using big data from real-world Australian rheumatology encounters to enhance clinical care and research.

OBJECTIVES: OPAL (Optimising Patient outcomes in Australian rheumatoLogy) Rheumatology is an independent not for profit Australian clinical research organisation which is the custodian of one of the largest datasets of patients with rheumatic diseases in the world, containing real-world clinical data from more than >175,000 unique patients collected over more than 900,000 clinical consultations. We describe the evolution and outcomes of the OPAL dataset, with particular reference to the use of big data derived from real-world clinical encounters to enhance clinical care and research. METHODS: De-identified data are regularly extracted and aggregated from the electronic medical records (EMR) of consenting patients treated by approximately 100 rheumatologists around Australia. The EMR shared by OPAL clinicians was specifically customised for rheumatology and collects comprehensive information on demographics, disease history, activity and severity, co-morbidities, pathology, and medication use. In addition, OPAL captures multifaceted outcomes data from the patient perspective through a novel electronic patient-reported outcome (ePRO) delivery system which allows for health-related quality of life measures to be matched with clinical indices. RESULTS: Since inception in 2009, OPAL has produced 35 publications and abstracts. OPAL also provides real-world data to determine drug utilisation, efficacy and safety, elucidate the natural history of disease, highlight areas of unmet need, guide medical affairs and commercial strategy, and to support regulatory and reimbursement submissions. CONCLUSIONS: The extensive, evolving and organic OPAL dataset reflects the complexities of clinical rheumatological practice. It provides unique opportunities to enhance clinical care and research.

Exploring the role of mononuclear phagocytes in the epididymis.

The onslaught of foreign antigens carried by spermatozoa into the epididymis, an organ that has not demonstrated immune privilege, a decade or more after the establishment of central immune tolerance presents a unique biological challenge. Historically, the physical confinement of spermatozoa to the epididymal tubule enforced by a tightly interwoven wall of epithelial cells was considered sufficient enough to prevent cross talk between gametes and the immune system and, ultimately, autoimmune destruction. The discovery of an intricate arrangement of mononuclear phagocytes (MPs) comprising dendritic cells and macrophages in the murine epididymis suggests that we may have underestimated the existence of a sophisticated mucosal immune system in the posttesticular environment. This review consolidates our current knowledge of the physiology of MPs in the steady state epididymis and speculates on possible interactions between auto-antigenic spermatozoa, pathogens and the immune system by drawing on what is known about the immune system in the intestinal mucosa. Ultimately, further investigation will provide valuable information regarding the origins of pathologies arising as a result of autoimmune or inflammatory responses in the epididymis, including epididymitis and infertility.

ROS1 signaling regulates epithelial differentiation in the epididymis.

The initial segment (IS) of the epididymis plays an essential role in male fertility. The IS epithelium is undifferentiated and nonfunctional at birth. Prior to puberty, the epithelium undergoes differentiation that leads to the formation of a fully functional organ. However, the mechanistic details of this program are not well understood. To explore this further, we used genetic engineering to create a kinase dead allele of the ROS1 receptor tyrosine kinase in mice and studied the effects of ROS1 tyrosine kinase activity on the differentiation of the IS epithelium. We show that the expression and activation of ROS1 coincides with the onset of differentiation and is exclusively located in the IS of the maturing and adult mouse epididymides. Here we demonstrate that the differentiation of the IS is dependent on the kinase activity of ROS1 and its downstream effector MEK1/2-ERK1/2 signaling axis. Using genetic engineering, we show that germ line ablation of ROS1 kinase activity leads to a failure of the IS epithelium to differentiate, and as a consequence sperm maturation and infertility were dramatically perturbed. Pharmacological inhibition of ROS1 kinase activity in the developing epididymis, however, only delayed differentiation transiently and did not result in infertility. Our results demonstrate that ROS1 kinase activity and the ensuing MEK1/2-ERK1/2 signaling are necessary for the postnatal development of the IS epithelium and that a sustained ablation of ROS1 kinase activity within the critical window of terminal differentiation abrogate the function of the epididymis and leads to sterility.

Epithelial basal cells are distinct from dendritic cells and macrophages in the mouse epididymis.

The epithelium that lines the epididymal duct establishes the optimal milieu in which spermatozoa mature, acquire motility, and are stored. This finely tuned environment also protects antigenic sperm against pathogens and autoimmunity, which are potential causes of transient or permanent infertility. The epididymal epithelium is pseudostratified and contains basal cells (BCs) that are located beneath other epithelial cells. Previous studies showed that in the mouse epididymis, BCs possess macrophage-like characteristics. However, we previously identified a dense population of cells belonging to the mononuclear phagocyte (MP) system (comprised of macrophages and dendritic cells) in the basal compartment of the mouse epididymis and showed that a subset of MPs express the macrophage marker F4/80. In the present study, we evaluate the distribution of BCs and MPs in the epididymis of transgenic CD11c-EYFP mice, in which EYFP is expressed exclusively in MPs, using antibodies against the BC marker keratin 5 (KRT5) and the macrophage marker F4/80. Immunofluorescence labeling for laminin, a basement membrane marker, showed that BCs and most MPs are located in the basal region of the epithelium. Confocal microscopy showed that in the initial segment, both BCs and MPs project intraepithelial extensions and establish a very intricate network. Flow cytometry experiments demonstrated that epididymal MPs and BCs are phenotypically distinct. BCs do not express F4/80, and MPs do not express KRT5. Therefore, despite their proximity and some morphological similarities with peritubular macrophages and dendritic cells, BCs do not belong to the MP system.

Oxidative stress and male reproductive health.

One of the major causes of defective sperm function is oxidative stress, which not only disrupts the integrity of sperm DNA but also limits the fertilizing potential of these cells as a result of collateral damage to proteins and lipids in the sperm plasma membrane. The origins of such oxidative stress appear to involve the sperm mitochondria, which have a tendency to generate high levels of superoxide anion as a prelude to entering the intrinsic apoptotic cascade. Unfortunately, these cells have very little capacity to respond to such an attack because they only possess the first enzyme in the base excision repair (BER) pathway, 8-oxoguanine glycosylase 1 (OGG1). The latter successfully creates an abasic site, but the spermatozoa cannot process the oxidative lesion further because they lack the downstream proteins (APE1, XRCC1) needed to complete the repair process. It is the responsibility of the oocyte to continue the BER pathway prior to initiation of S-phase of the first mitotic division. If a mistake is made by the oocyte at this stage of development, a mutation will be created that will be represented in every cell in the body. Such mechanisms may explain the increase in childhood cancers and other diseases observed in the offspring of males who have suffered oxidative stress in their germ line as a consequence of age, environmental or lifestyle factors. The high prevalence of oxidative DNA damage in the spermatozoa of male infertility patients may have implications for the health of children conceived in vitro and serves as a driver for current research into the origins of free radical generation in the germ line.

The presence of a truncated base excision repair pathway in human spermatozoa that is mediated by OGG1.

DNA repair has long been considered impossible in human spermatozoa due to the high level of DNA compaction observed in these cells. However, detailed examination of the base excision repair pathway in human spermatozoa has revealed the presence of an enzyme critical to this pathway, 8-oxoguanine DNA glycosylase 1 (OGG1). This glycosylase was associated with the sperm nucleus and mitochondria and could actively excise 8-hydroxy-2'-deoxyguanosine (8OHdG), releasing this adduct into the extracellular space. This activity was significantly reduced in the presence of cadmium (II), a recognized inhibitor of OGG1, in a time- and dose-dependent manner (P<0.001). Remarkably, spermatozoa do not possess the downstream components of the base excision repair pathway, apurinic endonuclease 1 (APE1) and X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1). The absence of these proteins was particularly significant, as APE1 is required to create a 3'-hydroxyl (3'-OH) terminus at the apurinic site created by OGG1, which would be recognized by the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. As a result, TUNEL was unable to detect oxidatively induced DNA damage in spermatozoa following exposure to hydrogen peroxide. In the same cells, intracellular and extracellular 8OHdG could be clearly detected in a manner that was highly correlated with the outcome of the sperm chromatin structure assay (SCSA). However, incubation of these cells for 48 hours revealed a time-dependent increase in TUNEL positivity, suggesting the perimortem activation of a nuclease. These results emphasize the limited capacity of mature spermatozoa to mount a DNA repair response to oxidative stress, and highlight the importance of such mechanisms in the oocyte in order to protect the embryo from paternally mediated genetic damage.