Nonmedical Switching From Originators to Biosimilars: Does the Nocebo Effect Explain Treatment Failures and Adverse Events in Rheumatology and Gastroenterology?

The act of nonmedical switching, defined as switching stable patients who are generally doing well with their current therapy from an originator biologic to its biosimilar, has been endorsed as a reasonable treatment strategy. The safety and efficacy of nonmedical switching have been evaluated in randomized controlled and real-world evidence studies, which have demonstrated that although many patients maintain treatment response after the switch, some patients experience therapy failure, resulting in therapy discontinuation. It has been postulated that the vast majority, if not all, of these treatment failures result from a "nocebo effect", defined as patients' negative expectations toward the therapy change. Reports suggest that the risk of a nocebo effect is higher following a mandated nonmedical switch. Although the nocebo effect is a well-recognized phenomenon in pain studies, evidence is limited in immune-mediated diseases primarily because it is difficult to quantify, especially retrospectively. In spite of this, numerous biosimilar studies in patients with immune-mediated diseases have concluded that nonmedical switching failures are due to a nocebo effect. The objective of this narrative review was to explore the reasons for nonmedical switch failure or discontinuation and the role of the nocebo effect among patients with inflammatory rheumatic and gastrointestinal diseases who switched from an originator biologic to its biosimilar.

Effect of disease duration and prior disease-modifying antirheumatic drug use on treatment outcomes in patients with rheumatoid arthritis.

OBJECTIVES: To determine if disease duration and number of prior disease-modifying antirheumatic drugs (DMARDs) affect response to therapy in patients with established rheumatoid arthritis (RA). METHODS: Associations between disease duration or number of prior DMARDs and response to therapy were assessed using data from two randomised controlled trials in patients with established RA (mean duration, 11 years) receiving adalimumab+methotrexate. Response to therapy was assessed at week 24 using disease activity outcomes, including 28-joint Disease Activity Score based on C-reactive protein (DAS28(CRP)), Simplified Disease Activity Index (SDAI) and Health Assessment Questionnaire Disability Index (HAQ-DI), and proportions of patients with 20%/50%/70% improvement in American College of Rheumatology (ACR) responses. RESULTS: In the larger study (N=207), a greater number of prior DMARDs (>2 vs 0-1) was associated with smaller improvements in DAS28(CRP) (-1.8 vs -2.2), SDAI (-22.1 vs -26.9) and HAQ-DI (-0.43 vs -0.64) from baseline to week 24. RA duration of >10 years versus <1 year was associated with higher HAQ-DI scores (1.1 vs 0.7) at week 24, but results on DAS28(CRP) and SDAI were mixed. A greater number of prior DMARDs and longer RA duration were associated with lower ACR response rates at week 24. Data from the second trial (N=67) generally confirmed these findings. CONCLUSIONS: Number of prior DMARDs and disease duration affect responses to therapy in patients with established RA. Furthermore, number of prior DMARDs, regardless of disease duration, has a limiting effect on the potential response to adalimumab therapy.

Effectiveness of biologics in Australian patients with rheumatoid arthritis: a large observational study: REAL.

BACKGROUND: The comparative effectiveness of biologic treatment regimens in a real world Australian population is unknown. AIM: To assess the effectiveness of biological disease-modifying anti-rheumatic drugs (bDMARD) as monotherapy or in combination with methotrexate and/or other conventional DMARD (cDMARD) for the treatment of rheumatoid arthritis (RA). METHODS: A retrospective, non-interventional study was conducted that investigated the use of bDMARD in adult patients with RA in routine clinical practice. Data were extracted from the Optimising Patient Outcomes in Australian Rheumatology - Quality Use of Medicines Initiative database. Real-world effectiveness was measured using the 28-joint disease activity score (DAS28) and clinical disease activity index (CDAI) by treatment group at baseline, weeks 12 and 24. RESULTS: A total of 2970 patients was included with a median (min-max) age of 60.0 (19.0-94.0) years and median (min-max) duration of RA before first bDMARD treatment of 6.0 (0.2-58.3) years. A total of 1177 patients received more than one bDMARD during the analysis period of 1 January 1997 to 15 August 2015. Patients had 4922 treatment 'episodes' (defined as a cycle of continuous individual bDMARD prescribing in a single patient). Patients received a mean (SD) of 1.7 (1.0) episodes of treatment with median (min-max) treatment duration of 0.7 (0-11.8) years; median treatment duration was higher with the first treatment episode. bDMARD were most commonly initiated in combination with methotrexate (73.9% of episodes) and least commonly as monotherapy (9.9% of episodes). Median (min-max) baseline DAS28 decreased from 5.3 (0-8.7) with the first bDMARD to 3.7 (0-8.8) with the second. Median baseline CDAI similarly decreased. CONCLUSIONS: Patients tended to persist longer on their first bDMARD treatment. bDMARD as monotherapy or in combination appear to be accepted treatment strategies in the real world.

The CEDAR Study: A Longitudinal Study of the Clinical Effects of Conventional DMARDs and Biologic DMARDs in Australian Rheumatology Practice.

OBJECTIVES: To observe the choices of conventional disease modifying antirheumatic drugs (cDMARDs) and biologic DMARDs (bDMARDs) in the management of rheumatoid arthritis (RA) in Australian routine clinical practice, to assess treatment survival and determine the effect of cDMARDs/bDMARDs on disease activity. METHODS: Routinely collected, deidentified clinical data was sourced from 20 Australian rheumatology practices. RA patients aged ≥18 years, who had received cDMARDs/bDMARDs and a recorded subsequent visit, were included. A linear mixed model was used to determine the change over time and the percentage reduction in disease activity was summarized. RESULTS: 12,526 RA patients were included: 72% females, mean age 62 years. cDMARDs and bDMARDs were used in 92% and 30% of patients, respectively. The most commonly prescribed cDMARD was methotrexate (76% patients); median time to stopping treatment was 337 months [95% CI: 279-ND]. Etanercept was the most commonly prescribed bDMARD (12% patients); median time to stopping treatment was 79 months [95% CI: 57-93]. Of 5,341 patients with a first change in medication (cDMARD or bDMARD), 87% had therapy escalation and 13% deescalation. Reduction in DAS28-ESR, 6-month post-DMARDs initiation ranged from 3%, adalimumab, to 14%, leflunomide and tocilizumab. CONCLUSIONS: In this large Australian cohort of unselected community RA patients, the choices of cDMARDs/bDMARDs are aligned with current international guidelines.

Longitudinal study of clinical prognostic factors in patients with early rheumatoid arthritis: the PREDICT study.

AIM: To assess the association between baseline clinical prognostic factors and subsequent Disease Activity Score of 28 joints (DAS28) remission in early rheumatoid arthritis (RA). METHODS: Data were collected using point of care clinical software from participating rheumatology centres. Patients aged 18 years or over whose date of clinical onset of RA was within the previous 12-24 months, who had at least 6 months of follow-up data and a DAS28-ESR (erythrocyte sedimentation rate) score recorded between 12 and 24 months from first being seen for RA were included. Data collected included baseline demographics, mode of disease onset, pattern of joint involvement at onset, smoking status, DAS28, rheumatoid factor (RF), anti-citrullinated peptide antibodies (ACPA), time from symptom onset to presentation and disease activity at baseline. Univariate and multivariate logistic regression of DAS28-ESR remission between 12 and 24 months after first assessment were performed. RESULTS: Data from 1017 patients were analyzed: 70% female; mean age 60 years (SD: 14.7); 70% RF-positive, 58% ACPA-positive. The strongest age and sex adjusted baseline predictors of DAS28-ESR remission at 12-24 months were remission at baseline (odds ratio [OR]: 4.49, 95% CI: 2.17-9.29, P < 0.001), being male (OR: 2.42, 95% CI: 1.46-4.01, P < 0.001), abstaining from alcohol (P < 0.001) and being lower weight (OR: 0.98, 95% CI: 0.97-1.00, P = 0.015). There was no statistically significant association between joint onset patterns, mode of onset, RF, ACPA or smoking status. CONCLUSION: In this observational study, patients with early RA at risk of not achieving remission include those with high disease activity at baseline, women, those who drink alcohol and those with higher body weight.

Patients with Rheumatoid Arthritis in the Australian OPAL Cohort Show Significant Improvement in Disease Activity over 5 Years: A Multicenter Observational Study.

OBJECTIVE: To evaluate disease activity trends in a large cohort of Australian patients with rheumatoid arthritis (RA) from 2009 to 2014. METHODS: This is a multicenter, cross-sectional, noninterventional study of patients with RA treated in Australia. Patients with RA treated at participating OPAL (Optimising Patient outcome in Australian RheumatoLogy) clinics were included in the study. Data, deidentified by patient, clinic, and clinician, were identified using a purpose-written electronic medical record. Patient demographics, disease onset, medications, and disease measures were analyzed. The Disease Activity Score at 28 joints (DAS28) was used to classify patients into the disease activity states of remission: low disease activity, moderate disease activity (MDA), and high disease activity. Choice of therapy was at the discretion of the treating clinician. RESULTS: At the time of analysis, the database contained 15,679 patients with RA, 8998 of whom fulfilled the inclusion criteria. Mean age was 63.2 years, mean disease duration was 13.8 years, and the majority were women (72.4%). A total of 37,274 individual DAS28-erythrocyte sedimentation rate scores were recorded for the 8998 patients. The frequency of remission increased significantly from 36.7% in 2009 to 53.5% in 2014 (p < 0.001), and that of MDA decreased from 33% (2009) to 22.2% (2014). The use of biologic disease-modifying antirheumatic drugs for the patients in remission increased from 17% in 2009 to 36.9% in 2014. CONCLUSION: Contemporary management of RA in Australia shows improvements in disease activity toward the target of remission over a 5-year period.

A comparison of searching the Cochrane library databases via CRD, Ovid and Wiley: implications for systematic searching and information services.

BACKGROUND: The Cochrane Library databases are available via different interfaces; evidence in the literature, together with anecdotal evidence, shows interfaces perform differently. To ensure the quality of searches, a study was undertaken to systematically explore the functionality of interfaces. OBJECTIVES: To demonstrate differences in functionality when searching the same databases across different interfaces; to discuss the implications this may have on searching; and in a wider context, to suggest a 'best match' for comparable searching. METHODS: Detailed cross-comparisons of a selection of search functions including MeSH terms, free text, proximity operators and truncation were undertaken in databases accessed via CRD, Wiley and Ovid. Up to three terms per function were selected and analysed. RESULTS: Differences were identified in the way searches for MeSH headings are executed, which fields are searched, how proximity operators perform, the word order searched and where terms are searched. This adds to a body of evidence demonstrating a lack of consistency in searching across different interfaces. CONCLUSIONS: A 'best match' for comparable searching is suggested. Differences between interfaces offering the same database content can have implications for the success of a search, on user education, and on database evaluation and purchasing decisions.

Barriers to optimal disease control for rheumatoid arthritis patients with moderate and high disease activity.

OBJECTIVE: To evaluate barriers that prevent rheumatoid arthritis (RA) patients from achieving Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) scores within the current recommended levels for low disease activity (LDA) or clinical remission (DAS28-ESR score <3.2). METHODS: Using an electronic medical record program, clinical data for RA patients treated in Optimising Patient Outcomes in Australian Rheumatology clinics, with a recorded DAS28-ESR score, were collected at one point in time. The data included demographics, medications, disease measures, and the rheumatologist's opinion of the main barriers preventing improvement to the recommended DAS28 score. RESULTS: Of the 4,037 patients with a recorded DAS28-ESR score, 304 patients (7.5%) had high disease activity (HDA) and 1,211 patients (30%) had moderate disease activity (MDA). For 584 HDA or MDA patients, the barriers to disease control (BTCs) were recorded by the rheumatologist when there was no adjustment to disease-modifying antirheumatic drug (DMARD) therapy. The recorded BTCs were irreversible joint damage (19.7%), patient-driven preference (14.7%), noninflammatory musculoskeletal pain (9.2%), insufficient time to assess the effect of recently initiated DMARDs (9.2%), safety concerns (7.5%), comorbidities (6.5%), resistant disease (6.3%), and other less common reasons. These patients received DMARDs (97.4%), including biologic agents (34.1%), methotrexate (74.8%), and oral corticosteroids (41.8%). CONCLUSION: This study identified clinical situations in which rheumatologists elected to continue RA patients with MDA or HDA on DMARD therapy without adjustment to achieve clinical remission or an LDA target of a DAS28-ESR score <3.2.

A retrospective chart review of the use of rituximab for the treatment of rheumatoid arthritis in Australian rheumatology practice.

AIM: Rituximab is one of nine biologic agents approved for the treatment of rheumatoid arthritis (RA) in Australia. The primary study objective was to analyze the factors that lead to the therapeutic decision to use rituximab in RA. METHOD: A cross-sectional, retrospective chart review was conducted to identify patients who were treated with rituximab and to evaluate their response to treatment. RESULTS: Factors influencing the prescription of rituximab were identified. The most commonly reported reason for prescribing rituximab was the presence of comorbidities and the presence of seropositive disease. Median rituximab treatment duration was 32.5 months and mean number of treatment cycles was 4.1. Disease activity scores showed significant improvement from baseline to most recent visit. Rituximab treatment was well-tolerated in this group of RA patients. CONCLUSIONS: Rituximab was effective in a refractory group of RA patients and appears to be safe in a population with a high prevalence of comorbidities, including malignancy and recurrent infections/bronchiectasis. This study may assist rheumatologists in selecting appropriately targeted therapy in RA.

A multi-center, observational study shows high proportion of Australian rheumatoid arthritis patients have inadequate disease control.

OBJECTIVES: To evaluate the disease activity and current pharmacological interventions used to achieve remission in rheumatoid arthritis (RA) patients in Australia. METHODS: Rheumatoid arthritis patients treated in participating Australian clinics were included in the study. Patient demographics, disease onset, medications and disease measures were analyzed. Data, de-identified to the patient, clinic and clinician were captured using an electronic clinical management program. The disease activity score (DAS28) was used to classify patients into the disease activity states of remission, low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA). Choice of therapy was at the discretion of the treating clinician. RESULTS: A total of 5686 patients, 72.9% female, 26.9% male, with mean age 61.1 (SD 13.6) years and mean disease duration of 11.5 (SD 10.5) years were analyzed. DAS28 ESR (erythrocyte sedimentation rate) scores were recorded for 2973 patients, with 41.6% in remission, 18.6% LDA, 31.6% MDA and 8.2% HDA. Of those in remission, 17% received a biological disease modifying anti-rheumatic drug (bDMARD), 73% methotrexate (MTX), 19% leflunomide (LEF) and 28% prednisolone. Of the patients with MDA, 20% received a bDMARD, 76% MTX, 24% LEF and 39% prednisolone. Of the patients in HDA, 27% received a bDMARD, 78% MTX, 31% LEF and 60% with prednisolone. CONCLUSIONS: Cross-sectional assessment of this large cohort of Australian RA patients found a large proportion remain in moderate or high disease activity; suggesting a considerable evidence-practice gap. Improvement in disease control in this group may reduce future health burdens.

The SMILE study -- safety of methotrexate in combination with leflunomide in rheumatoid arthritis.

OBJECTIVE: To assess the safety of treating patients with rheumatoid arthritis with a combination of methotrexate (MTX) and leflunomide (LEF) in comparison to MTX monotherapy, in clinical practice. METHODS: The Safety of Methotrexate in Combination with Leflunomide in Rheumatoid Arthritis (SMILE) study was a multicenter, observational, cross-sectional, retrospective safety study. The study was conducted by the Optimising Patient Outcomes in Australian Rheumatology-Quality Use of Medicines Initiative (OPAL QUMI). Data were deidentified for patient, clinic, and clinician prior to collection from 13 participating rheumatology practices (25 rheumatologists). Comparative analysis of safety for the different treatments, primarily with regard to neutropenia and liver abnormalities, was performed. RESULTS: In total, 2975 patients were included in the study: 74% female, 26% male, mean age 62 years (SD 13.6). Distribution of therapy: MTX monotherapy 52.2%, LEF monotherapy 7.3%, MTX plus LEF 13.9%, and neither MTX nor LEF 26.6%. Comorbid liver disease was reported in 8.1% of patients. Liver function abnormalities were reported in 12% of the MTX monotherapy group, 16% of the LEF monotherapy group, 19% of the MTX-LEF combination group, and 14% of the group not taking either drug. Neutropenia was reported in 2.3% of the MTX monotherapy group, 5.5% of the LEF monotherapy group, 3.9% of the MTX-LEF combination group, and 4.2% of the group not taking either drug. CONCLUSION: The combination of MTX and LEF was well tolerated, with adverse events comparable to those of monotherapy and the other nonbiologic disease-modifying antirheumatic drug treatment group.

Perceptions of methotrexate use in rheumatoid arthritis by rheumatologists and their patients: an Australian survey study.

AIM: To improve treatment for rheumatoid arthritis (RA), rheumatologists have embraced patient-reported outcomes; however, limited data are available on patient perceptions of treatment. Our objective was to assess the use and perceptions of methotrexate (MTX) by patients with RA (primary objective) and their rheumatologists, patient-reported adverse events (AEs) related to MTX, and patient-reported use of alcohol, folic acid and biologic agents. METHOD: Each rheumatologist completed a rheumatologist questionnaire and then asked patients with RA to complete a patient questionnaire. RESULTS: Questionnaires were completed by 46/50 rheumatologists and 1313/1313 patients. Patients (72% female, 38% > 10 years RA) took oral MTX regularly (72% never miss a dose) and at therapeutic doses. Most patients (79%) were currently taking MTX, but 36% of patients were on low doses (≤ 10 mg/week) and 8% intentionally and regularly did not take MTX. Most patients had a positive perception of MTX; 82% of patients considered MTX to be important; 60% preferred to continue taking MTX. Although AEs (generally mild and gastrointestinal) occurred regularly (38%) and in some patients continuously (13%), 41% of patients did not experience an AE. Patients abstained from alcohol (46%) and took folic acid (91%, but with variable dosage regimens and doses). There were 29% of patients taking biologic agent therapy; only 70% of these patients were also taking MTX. CONCLUSION: MTX was well used, well tolerated and well perceived. However, to ensure that MTX therapy is as effective as possible, rheumatologists should discuss MTX use with their patients and consider alternative strategies for some patients.

Hereditary periodic fever syndrome sans fever or distinct periodicity presenting with psychosis.

The genetic basis for several hereditary periodic fever syndromes has been identified and consequently, the phenotypic spectrum of these disorders has broadened. We describe a young woman with tumor necrosis factor receptor-associated periodic syndrome (TRAPS), proven by mutational analysis, who presented with psychosis but without fever, symptom periodicity, or similar family medical history. This patient represents the first case of TRAPS-associated psychosis. This case illustrates the importance of mutation analysis for this group of disorders in individuals presenting with unexplained inflammatory symptoms and recurrent psychoses.