Use of leflunomide plus TNF-α inhibitors in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory immune-mediated systemic disease which primarily affects the joints. Leflunomide (LFN) is a disease modifying anti-rheumatic drugs (DMARDs) which acts by inhibiting the synthesis of pyrimidines. Several trials have demonstrated the efficacy and safety of LFN alone or in combination with biological agents such as tumor necrosis factor-α (TNF-α) inhibitors in the treatment of RA patients. TNF-α is a pro-inflammatory cytokine known to a have a key role in the pathogenesis of RA. TNF-α inhibitors have demonstrated efficacy as monotherapy or in combination with other anti-inflammatory or DMARDs in the treatment of RA. Five TNF-α inhibitors are available for clinical use and include infliximab, adalimumab, golimumab, certolizumab pegol and etanercept. In this editorial, we briefly discuss the efficacy and safety of LFN and TNF-α inhibitors in the treatment of RA, and the potential beneficial effect of both LFN and TNF-α inhibitors in improving the endothelial dysfunction and in reducing the risk of acute cardiovascular and/or cerebrovascular events.

Keywords::

• leflunomide
• opportunistic infections
• rheumatoid arthritis
• TNF-α inhibitors

1. Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory immune-mediated systemic disease which primarily affects the joints. Despite the treatment and episodes of remission, it leads to progressive joint destruction resulting in functional impairment and disability. Disease modifying anti-rheumatic drugs (DMARDs) may prevent or decrease joint damage, help maintain regular structure and functions of joints and avoid long-term disability. Leflunomide (LFN) is a DMARD that has been approved for the therapy of RA since 1996 and acts by inhibiting the synthesis of pyrimidines [1]. LFN undergoes rapid hepatic metabolism to the active compound teriflunomide (A77 – 1726). The orally loading dose of LFN is 100 mg for 3 days and the maintenance dose is 10 – 20 mg/day. Clinical effects of LFN appear rapidly and comparable with those of methotrexate (MTX) and sulfasalazine (SSZ) in the treatment of RA [2-5]. Golicki et al. [6] confirmed that LFN efficacy was not different from that observed with MTX and SSZ. LFN decreases the disease activity and inhibits progression of radiographic changes to the same extent as medium doses of MTX. Furthermore, the combination of MTX and LFN is recommended if MTX alone in full dose does not allow to reach the complete clinical remission. According to the EULAR recommendations, when MTX contraindications or intolerance are present, LFN or SSZ should be considered as part of first-line treatment [7]. Londono et al. [8] treated with MTX plus LFN 88 patients with active RA and confirmed the efficacy of this combination regimen in the treatment of RA. Given the importance of early and effective treatment of RA, optimizing the time to diagnosis seems to be needed. Kellner et al. [9] treated with LFN 334 patients with early RA. A considerable rate of responders (71.9%) was seen after 12 weeks of therapy and increased further after 24 weeks (84.6%). In particular, the rate of patients with good response (DAS28 ≤ 3.2) after 24 weeks of therapy was greater in DMARD-naïve patients and concomitant treatment with corticosteroids or MTX did not have an effect on DAS28-response. Furthermore, LFN may be used for the treatment of patients with RA on chronic dialysis without any dosage modification. Indeed, Bergner et al. [10] measured teriflunomide during standard hemodialysis sessions and calculated teriflunomide clearances in 5 RA patients and end-stage renal disease. They proved that teriflunomide is removed by hemodialysis to a very small amount, confirming that no additional LFN administration is required following dialysis. Infections are one of the common adverse events observed in patients treated with LFN and are also the major cause of the increased mortality in patients with RA. Yoo et al. [11] analyzed 401 patients with RA treated with LFN and reported that 33% of these patients developed severe infections such as sepsis, pneumonia, oral candidiasis, pyelonephritis, pulmonary tuberculosis (TB) and cryptococcosis. In particular, 33 of the 401 patients treated with LFN developed severe infections and among them 12 patients had bacterial pneumonia, 2 patients had viral pneumonia, 3 patients pulmonary TB and 5 patients presented oral candidiasis. One patient died for concomitant pulmonary TB and bacterial pneumonia. However, older age, diabetes mellitus, higher daily dosage of corticosteroids further increase the risk of severe infections. Furthermore, the severity of RA correlates with the degree of inflammation and active inflammation may increase the risk of infections. Lee et al. [12] reported that the cumulative dose of LFN may favor the development and progression of silent liver fibrosis in RA patients treated with MTX. During the last decade many new biological immune modulators entered the market as new therapeutic principles. Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine known to a have a key role in the pathogenesis of various immune-mediated or inflammatory diseases such as RA [13-19]. TNF-α inhibitors have demonstrated efficacy in large, randomized controlled clinical trials either as monotherapy or in combination with other anti-inflammatory or DMARDs in the treatment of chronic immune-mediated or inflammatory diseases [13-19]. There are five TNF-α inhibitors available for clinical use including anti-TNF-α monoclonal antibodies (mAbs) (infliximab, adalimumab, golimumab and certolizumab pegol) and a fusion protein that acts as a ‘decoy receptor' for TNF-α (etanercept) [13-19]. Potential side effects associated with the use of TNF-α inhibitors include infusion reactions with infliximab, injection site reactions to subcutaneously administered drugs, re-activation of latent TB, increased frequency of opportunistic infections, malignancies, autoimmune diseases, neutropenia and demyelinating diseases [13-19]. Appropriate screening with Mantoux test and chest X-ray should be performed before starting treatment. The appearance of neutralizing antibodies has been described in patients treated with infliximab, which is a chimeric human/mouse mAb, as well as in those treated with adalimumab, in spite of its fully human sequence [13,15]. Therefore, the administration of an immunosuppressive drug like MTX is warranted to prevent their development [13,15]. LFN might be the therapeutic alternative to the use of MTX to prevent the development of neutralizing antibodies against infliximab, even if, no data are reported in literature. Clinical trials would be useful to confirm the efficacy of LFN in suppressing the production of neutralizing antibodies against infliximab [20,21]. Kalden et al. [20] treated 70 RA patients with LFN and infliximab and reported that this combination therapy may result in significant clinical benefit for the majority of patients, thus presenting an alternative to the usual MTX-infliximab combination. Establishing LFN therapy prior to initiation of infliximab infusions may help to prevent side effects. Sokolove et al. [22] confirmed the efficacy and safety of treatment with LFN or MTX plus one TNF-α inhibitor (infliximab, etanercept or adalimumab). In particular, the incidence of increase in transaminases resulted uncommon. Benucci et al. [23] evaluated 96 RA patients who were treated with etanercept or adalimumab with LFN or MTX. The analysis demonstrated an improvement in DAS28 in both patients treated with LFN and MTX (33.3% of patients receiving LFN and 51.8% receiving MTX). However, the improvement in DAS28 seems to be independent of the administration of etanercept or adalimumab. The authors also confirmed the safety of combinations regimen. Notably, LFN could exert important vasculoprotective effects because it inhibits the nuclear factor κB signal transduction pathway, decreases the subendothelial migration of peripheral blood mononuclear cells and, finally, causes functional impairment of antigen-presenting cells [24]. Therefore, LFN is an anti-atherogenic drug and its administration could decrease the risk of developing [24]. Furthermore, TNF-α inhibitors reduce the expression of vascular endothelial growth factor (VEGF), nitric oxide (NO) and inducible NO synthase [25,26]. VEGF, which is a critical mediator of inflammation both in chronic immune-mediated and allergic diseases, is a pro-angiogenic factor which alters the microvascular network and contributes to the development and progression of atherosclerosis [25,27,28]. Etanercept and adalimumab may exert beneficial effects on lipid profile improving the endothelial dysfunction [29]. TNF-α inhibitors improves both the clinical course of RA and the endothelial function and, thus, may decrease the risk of acute cardiovascular and/or cerebrovascular events [25,30-32]. These findings suggest that the therapeutic combination LFN plus one TNF-α inhibitor could play a beneficial role in the treatment of accelerated atherosclerosis in patients with RA or other immune-mediated diseases. Lymphotoxin (LT)-α seems to play a role in the development of RA. Indeed, in RA, in addition to TNF-α, also LT-α expression in the synovium is elevated [33]. T-helper (Th)-1 and Th-17 lymphocytes have been associated with autoimmune diseases such as RA and expressed LT-α [34,35]. Depletion of LT-α-expressing Th-1 and Th-17 lymphocytes with LT-α-specific mAb may be beneficial in the treatment of autoimmune disease such as RA [35]. However, it would seem that TNF-α inhibitors could bind LT-α as we have proven in PsA patients [36]. Although TNF-α inhibitors are generally well tolerated, physicians should be aware of the potential adverse events of these drugs [13-19].

2. Expert opinion

DMARDs may prevent or decrease joint damage in patients with RA. LFN inhibits the synthesis of pyrimidines and undergoes rapid hepatic metabolism to the active compound teriflunomide. Several trials confirmed that LFN efficacy is not different from that observed with other DMARDs such as MTX and SSZ. Indeed, LFN inhibits progression of radiographic changes to the same extent as medium doses of MTX and combination of MTX and LFN is recommended if MTX alone in full dose does not allow to reach the complete clinical remission. Furthermore, LFN may be used for the treatment of patients with RA on chronic dialysis without any dosage modification. However, infections are one of the common adverse events observed in patients treated with LFN. TNF-α inhibitors have demonstrated efficacy in large, randomized controlled clinical trials either as monotherapy or in combination with other anti-inflammatory or DMARDs in the treatment of chronic immune-mediated or inflammatory diseases. LFN and infliximab may represent a valid alternative to MTX–infliximab combination. LFN and TNF-α inhibitors also improve endothelial function and may decrease the risk of acute cardiovascular and/or cerebrovascular events. Although TNF-α inhibitors are generally well tolerated, physicians should be aware of the potential adverse events of these drugs such as reactivation of latent TB infection.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.