Characteristics Associated with Biologic Monotherapy Use in Biologic-Naive Patients with Rheumatoid Arthritis in a US Registry Population

Introduction The aim of this study was to describe factors associated with initiating a biologic as monotherapy vs in combination with a conventional disease-modifying antirheumatic drug (DMARD) in biologic-naive patients with rheumatoid arthritis (RA) enrolled in the Corrona registry. Methods First biologic initiations were classified as monotherapy (Bio MT) or combination therapy (Bio CMB). Baseline demographic and clinical characteristics were evaluated. Odds ratios (OR) based on mixed effects regression models estimated the association of covariates and use of monotherapy. Median odds ratios (MOR) based on estimated physician random effects quantified variation in individual physician use of monotherapy. Results Between October 2001 and April 2012, 3,923 previously biologic-naive patients initiated biologic therapy, of which 19.1 % initiated as monotherapy. Baseline characteristics of patients initiating Bio MT and Bio CMB were similar for age, sex, duration of RA, and clinical disease activity index. Significantly higher proportions of Bio CMB initiators had prior conventional DMARD (97.23 vs 85.60 %; P < 0.01) and methotrexate (MTX) use (91.68 vs 71.87 %; P < 0.01) compared with Bio MT initiators. Variation in individual physician use of monotherapy [MOR 1.89; 95 % confidence interval (CI), 1.66–2.23] and use of biologics approved by the United States Food and Drug Administration for monotherapy (OR 1.47; 95 % CI, 1.20–1.81) significantly influenced the odds of initiating Bio MT. Patient history of hepatic disease, neutropenia, and malignancy were associated with increased odds of being prescribed Bio MT. Conclusion In addition to regulatory approval for monotherapy and specific pre-existing comorbidities, significant variation in physician use of monotherapy was associated with increased likelihood of initiating Bio MT, independent of patient factors. Electronic supplementary material The online version of this article (doi:10.1007/s40744-015-0008-9) contains supplementary material, which is available to authorized users.

International task forces recommend conventional disease-modifying antirheumatic drugs (DMARDs) as first-line therapy in patients with RA, which should be started as soon as the diagnosis has been made with the goal of achieving remission or low disease activity [1,2]. However, a proportion of patients fail to respond to conventional DMARDs. In addition, a number of patients may not be able to tolerate conventional DMARDs due to medication toxicity, contraindicating comorbidities, or interactions with other medications [3]. In such patients, treatment with a biologic DMARD as monotherapy may provide clinical benefit while sparing the patient from undesirable side effects due to conventional DMARDs [4]. The aim of this study was to further investigate the factors that may influence the decision to start a biologic as monotherapy or in combination with conventional DMARDs in a real-world cohort of biologic-naive patients with RA.

Study Population
The Corrona registry is an independent, prospective observational cohort of patients with RA recruited at more than 160 private and academic practice sites across 40 states in the United States, with more than 600 participating

Patient Disposition and Baseline Characteristics
Between Of patients initiating Bio MT, the most common reasons for discontinuing any prior DMARDs were toxicity and lack of efficacy, with a significant proportion of discontinuations due to patient or physician preference (Fig. 1a).
Furthermore, the most frequently reported Of patients who initiated Bio CMB, toxicity (36.6 %) was the most frequently reported reason for discontinuing prior MTX and lack of efficacy (31.5 %) was the most common reason for discontinuing prior sulfasalazine; however, reasons not related to toxicity or efficacy (e.g., physician preference) were the most common reasons for discontinuing leflunomide and hydroxychloroquine (Fig. 1b).

Physician Characteristics in Prescribing
Biologic Therapy in Biologic-Naive Patients  was associated with biologic initiation as monotherapy in model 3. Table 3

Current European League Against Rheumatism (EULAR)
and American College of Rheumatology guidelines for the management of RA emphasize that treatment should be a shared decision between physicians and patients, and should aim at reaching a target of low disease activity or remission [1,2].  conventional DMARDs is better than either treatment alone [5][6][7]. The EULAR Task Force mentions that if monotherapy must be started, then some supportive evidence for such a strategy exists only for tocilizumab [2].
The goal of this study was to describe the frequency of monotherapy biologic initiation in a real-world setting and to identify whether any factors beyond toxicities and intolerance to conventional DMARDs may influence the decision to start a biologic as monotherapy. In this US-based registry analysis, Bio MT was common and was initiated in approximately 1 of 5 biologic-naive patients with RA initiating a biologic agent. In previous biologics registry and claims database studies, 12-39 % of patients who were taking biologics did so as monotherapy [3,[10][11][12][13][14][15][16]. As expected, we identified that patients who received Bio MT frequently had prior toxicity to conventional DMARDs. Prior conventional DMARDs were also commonly discontinued due to lack of efficacy. However, reasons not related to either toxicity or efficacy, such as physician preference and patient preference, were frequently reported as reasons for discontinuing prior conventional DMARDs.
In multivariate analyses, initiation of Bio MT in this biologicnaive population was associated with the presence of comorbidities, including history of hepatic disease, neutropenia, and malignancy. In addition to the findings above, significant variation in physician use of monotherapy influenced the odds of initiating Bio MT in biologic-naive patients. This was assessed by calculating the estimated physician random This study analyzed initiations of only the first biologics for each participating patient; however, as RA is a chronic disease, treatment strategies are dynamic in nature and patients may have monotherapy treatment regimens prescribed intermittently alternating with combination regimens. The reasons patients initiate monotherapy with different biologics may vary and be biologic specific, including preference for a particular route or frequency of administration. Additionally, the patientphysician decision-making process often involves a complex dialog, and there may be reasons for changing from DMARDs to biologics that may not be possible to be fully described or captured.

CONCLUSION
In conclusion, initiating biologic monotherapy in the biologic-naive population of this study was significantly influenced by variation in physician use of monotherapy, as well as whether the biologic was approved for monotherapy in the United States and history of hepatic disease, neutropenia, or malignancy.
Further prospective analyses will follow prescription patterns to compare efficacy outcomes of patients initiating Bio MT with those initiating Bio CMB and evaluate whether Bio MT is associated with less toxicity.