Efficacy and Treatment Costs of Monotherapy with bDMARDs in the Treatment of Rheumatoid Arthritis in Patients Intolerant to or Inappropriate to Continue Treatment with Methotrexate

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of synovial joints [1, 2]. The persistence of intra-articular inflammation causes cartilage destruction and bone erosion, leading to peripheral joint deformation and disability. Joint damage and functional loss are present at the very early stages, but the rate of progression of disease varies among individual patients [3, 4].

The global prevalence of RA in the adult population is estimated to be 0.5–1%; however, it appears to depend greatly on the geographical area (Japan 0.2%, Netherlands 1–1.5%, Scandinavian Peninsula 3%, Spain 0.5%, and United States 1%) [5, 6]. In Italy, two observational studies estimated a prevalence of 0.33% in Liguria and 0.31% in Lombardy [5, 7]. Despite its relatively low prevalence, RA is associated with significant disability and high economic and social impact [8]. Conventional disease-modifying anti-rheumatic drugs (cDMARDs), such as methotrexate (MTX), represent the first-line of treatment, whereas biologic disease-modifying anti-rheumatic drugs (bDMARDs) constitute second-line strategy and are recommended in all patients with inadequate response or who are intolerant, or for whom it would be inappropriate to continue treatment with cDMARDs [9, 10].

The use of bDMARDs has brought significant progress in RA therapy as they allow a very high proportion of patients to achieve clinical remission or low disease activity, with a concomitant reduction of long-term disability [11‐15]. In most cases, bDMARDs—including adalimumab (ADA), abatacept, infliximab, etanercept (ETN), certolizumab (CTZ), golimumab, rituximab, and tocilizumab (TCZ)—are administered in combination with MTX for the treatment of moderate to severe RA in adult patients with an inadequate response to MTX. In other cases, some of these agents (ADA, ETN, CTZ, and TCZ) can be used as monotherapy in the treatment of RA patients who are intolerant to MTX, or for whom it is inappropriate to continue treatment with MTX.

By focusing attention on this latter therapeutic indication, the aim of this analysis was to estimate the efficacy and treatment costs of monotherapy with bDMARDs in treatment of RA patients who are intolerant to MTX, or for whom it is inappropriate to continue MTX treatment.

The present analysis used the NNT as a synthetic indicator to assess the clinical benefits and costs associated with the use of different monotherapies (ADA, ETA, CTZ, and TCZ) in the treatment of patients who are intolerant to MTX, or for whom it is no longer appropriate to continue therapy with MTX. The NNT was calculated using both ACR response rates, indicated in the meta-analysis conducted by Orme et al. [20], and EULAR criteria, obtained from the meta-analysis conducted by NICE in its recent appraisal [19]. For each bDMARD, we calculated the respective 6-month costs for purchase, administration, and monitoring by the NHS.

TCZ had the lowest mean cost for the NNT calculated with both response criteria, which were slightly higher for the iv formulation after administration and monitoring. The costs calculated for the other sc bDMARDs were significantly higher. Hence, it was seen that the greater the clinical improvement, according to ACR (20, 50, or 70) or EULAR criteria (moderate or good response), the greater the difference in NNT costs in favor of TCZ (sc/iv).

While it is worthwhile to discuss the results of economic analysis by comparing them with those already published, to the best of our knowledge there are no other similar assessments in this specific patient population. However, three cost-utility analyses that estimated the incremental cost per QALY for TCZ compared to other TNF-α inhibitors are available. In the first study, carried out in Greece, TCZ had an incremental cost per QALY of €28,837 compared to the use of other TNF-α inhibitors in the treatment of patients intolerant to MTX or for whom it was not appropriate to continue treatment with MTX [31]. The second analysis, carried out in the United States, compared monotherapy with TCZ or ADA for the treatment of patients with RA for whom treatment with MTX was not appropriate [32]. The authors, on the basis of the results of the ADACTA direct comparison clinical study, calculated an incremental cost per QALY of US $36,944 in favor of TCZ compared with ADA. The third study [33], from the UK, evaluated the cost-utility of TCZ in addition to the current sequence of treatments envisaged for RA. In that report, two scenarios were explored: one for patients for whom MTX is contraindicated and one for tolerant patients. For each of these scenarios, three different treatment strategies were compared: (1) standard of care (consisting a sequence of the most commonly administered biologics), (2) TCZ as first-line therapy, and (3) TCZ as second-line therapy. In patients for whom MTX is contraindicated, TCZ was found to be cost-effective as both first- and second-line therapy, whereas in MTX-tolerant patients the strategy involving the addition of TCZ (first- or second-line) was found to be similar to that determined by the standard of care. All three analyses concluded that TCZ was a cost-effective option in patients with RA for whom biologic monotherapy was indicated, thus confirming the results of the present analysis with different methods.

To analyze the limits of our study, as previously mentioned the two meta-analyses considered did not allow determination of clinical outcomes expressed in terms of survival simple or QALY, essentially changing the choice of assessment method to the cost for the NNT as an indicator of cost-effectiveness. For this reason, we compared the bDMARDs by calculating the number of subjects needed to be treated to achieve a specific therapeutic target (ACR/EULAR). With this indicator, it was possible to determine an order of preference among the bDMARDs based on cost-effectiveness.

A further aspect that needs to be discussed is the efficacy data used to calculate the NNT. Although the two meta-analyses [19, 20] evaluated a large number of randomized clinical studies, the efficacy data are characterized by a broad range of variability. Given this uncertainty, sensitivity analysis was required to evaluate its impact on the final results. It was also seen that by simultaneously considering the upper or lower extremities of the efficacy rate variability range (ACR 20, 50, 70, moderate or good response), the results of the base case were more or less confirmed. Additionally, as confirmation of the clinical data used herein, a subsequent analysis conducted versus alternative monotherapies (ADA, ETA, CTZ) showed that TCZ had a greater likelihood of being the most effective treatment in inducing ACR 20, 50, and 70 responses [34].

Hence, it must be pointed out that the efficacy of TCZ, as mentioned in both meta-analyses, must be interpreted with a caution given the direct effect that the agent has on CRP values, as the latter is a component of the ACR and EULAR composite endpoints on which the comparison was based. To confirm the validity of the results of the meta-analyses, it is important to remember that in some of the most recent clinical studies investigating the efficacy of TCZ monotherapy (ACT-RAY and ADACTA studies) that the composite endpoints were calculated using ESR values only. This avoids potential bias due to CRP values, but at the same time confirmed the greater efficacy of TCZ [35, 36]. Hence, a post hoc analysis of the ADACTA study [36], which used the Clinical Disease Activity Index (CDAI) criterion (a parameter that does not consider values such as CRP or ESR to evaluate disease activity and remission rates), also confirmed the efficacy of TCZ, in agreement with the findings obtained in the ADACTA study [35].

Given the limited effect on total costs, no sensitivity analysis was conducted for monitoring and administration of drugs. To allow homogeneous comparison for the biologic agents, the cost considered was the NHS purchase cost net of compulsory legal discounts only. Because it is difficult to identify the actual drug cost that takes into account all the discounts granted to hospital structures, it was considered unreasonable to conduct sensitivity analysis on this parameter.

As this economic analysis was conducted from the Italian NHS perspective, the present results may not be directly generalized to other countries with different drug costs and healthcare services reimbursement. Furthermore, the analysis considered only the economic impact of a few direct medical costs (drugs, administration, and monitoring).

The results of the present economic assessment, estimating the mean costs of NNT showed that TCZ represents a cost-effective therapeutic option in an NHS perspective compared to other TNF-α inhibitors (ADA, ETA, CTZ) as first-line monotherapy for patients who are intolerant to MTX, or for whom it is inappropriate to continue treatment with MTX.