- Email: [email protected]
Immunomodulation of rheumatologic disorders with non-biologic disease modifying antirheumtic drugs
Author’s Accepted Manuscript Immunomodulation of rheumatologic disorders with non-biologic disease modifying antirheumtic drugs Ulrich A. Walker www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S0037-1963(16)30029-4 http://dx.doi.org/10.1053/j.seminhematol.2016.04.017 YSHEM50873
To appear in: Seminars in Hematology Cite this article as: Ulrich A. Walker, Immunomodulation of rheumatologic disorders with non-biologic disease modifying antirheumtic drugs, Seminars in Hematology, http://dx.doi.org/10.1053/j.seminhematol.2016.04.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Immunomodulation of rheumatologic disorders with non-biologic disease modifying antirheumtic drugs
Ulrich A. Walker Unispital Basel Dept. of Rheumatology Petersgraben 4 CH 4037 Basel Switzerland Tel.:
+41-61-2652525
Fax:
+41-61-2659021
E-Mail: [email protected]
Keywords: Antirheumatic agents, treatment outcome, mode of action
Abstract Although biological agents have revolutionized the immunomodulation of many rheumatic disorders, conventional disease modifying antirheumatic drugs (DMARDs) remain important glucocorticosteroid sparing agents and combination partners. In rheumatoid arthritis, low-dose glucocorticosteroids can be regarded as a DMARD due to preventive effects on joint erosions. Therapy with methothrexate and possibly also other DMARDs may alter the natural evolution of rheumatoid arthritis severity over time and therapy should be instituted as early as possible. Leflunomide is an equipotent alternative to methotrexate in rheumatoid arthritis, if methotrexate cannot be tolerated. Hydroxychloroquine inhibits toll-like receptor signaling and exerts antithrombotic and antihyperlipidemic effects, all thought to be beneficial in systemic lupus erythematosus. Hydroxychloroquine improves organ involvement in lupus, prevents lupus flares and reduces mortality. It should be given to every lupus patient without contraindications.
Introduction The management of rheumatoid arthritis (RA) and many other autoimmune diseases (AIDs) is frequently based on the use of glucocorticosteroids (GC) and disease-modifying antirheumatic drugs (DMARDs), with the latter being administered either as synthetic compounds, or as biological agents. GC are mostly used for the treatment initiation, as the onset of their effect is relatively rapid. The therapeutic onset of most DMARDs in contrast is frequently prolonged and may even take weeks [1]. Adding synthetic or biologic DMARDs to GC, or replacing GC treatment with DMARDs is common clinical practice in many AIDs in order to prevent or diminish GC side effects. Although biological agents have revolutionized the treatment of many rheumatic disorders, conventional DMARDs remain important anchor drugs in the therapeutic armamentarium and are mostly used as first-line GC-sparing agents prior to the use of biological agents. This article provides an overview of the most important conventional DMARDs.
Glucocorticosteroids GC treatment remain an important pillar in the treatment of RA not only due to their rapid onset of action, but also because of clear evidence that initial low-dose GC treatment slows the radiographic progression of the disease [2]. Low-dose initial GC treatment favorably alter the disease course for years, and this effect persists even after complete GC discontinuation [1]. Thus GC satisfy the conventional definition of a DMARD [2]. Long-term high-dose GC therapy is however associated with inevitable side effects. Continued GC exposure is even associated with a dose-dependent increase in all-cause mortality and also with cardiovascular death, as shown in RA [3]. The prednisone dose threshold associated with an increase in mortality was 8-15 mg per day, with an adjusted hazard ratio of 1.78 compared to RA patients without GC treatment [3]. For the cumulative GC dose, the minimum dosage associated with an increase in all-cause mortality was 40 grams [3]. In RA, interleukin-6 and other pro-inflammatory cytokines are detectable in high amounts in the early morning hour serum. The cytokine levels correlate with morning stiffness and other markers of RA activity [4]. The circadian increase of endogenous cortisol in the early morning hours however lags the increase of cytokines by 1-2 hours [4]. This observation and the fact that low dose prednisone is more effective when given at night compared to morning doses [5] have led to the development of an oral slow-release prednisone tablet. This formulation is taken at bedtime, releases prednisone at about 2am and efficiently counteracts the peak of proinflammatory cytokines in the early morning serum. Compared to conventional morning GC doses, the slow-release GC formulation enhances the control of morning stiffness and possibly also other measures of RA activity [4,6].
Methotrexate Methotrexate (MTX) binds to dihydrofolate reductase an enzyme necessary for the de novo synthesis of purine and pyrimidine nucleotides and for the maintenance of many other metabolic pathways [7]. In the low doses used in rheumatology, MTX inhibits mainly the purine biosynthesis [8]. MTX monotherapy shows a clinically important and statistically significant control of RA activity when compared with placebo, improves physical function, and counteracts radiographic progression [7]. Remission rates are however low when MTX is given alone [7]. Patients who do not respond to MTX alone typically improve with combinations of MTX and other DMARDs. Patients receiving MTX monotherapy are twice as likely to discontinue treatment due to adverse events compared to placebo (16% versus 8%), but have no differences in the total number of serious adverse events [7]. Several studies have suggested that MTX provides a substantial survival benefit in patients with RA [9,10]. The optimal dose for MTX is debated for a long time. Multinational recommendations for its use recommend that MTX should be started orally at 10–15 mg/week, with escalation of 5 mg every 2–4
weeks up to 20–30 mg/week, depending on the clinical response and tolerability [11]. One more recent study directly compared the relative bioavailability, safety and tolerability of oral MTX and subcutaneous MTX in patients with RA [12]. Systemic exposure of oral MTX plateaued at doses beyond 15 mg/week. Subcutaneous MTX in contrast demonstrated a linear increase in systemic exposure with serum levels greater than those of oral MTX dosing, particularly beyond 15 mg/week. Thus, patients with an inadequate clinical response to oral MTX may benefit from higher drug exposure by switching to subcutaneous MTX. A randomized blinded, placebo controlled comparison found that subcutaneous administration of MTX was significantly more effective in RA than oral MTX dosing [13]. Multinational recommendations recommend parenteral administration of MTX in the case of inadequate clinical response or intolerance to prior oral doses [11]. Delay of DMARD therapy is a major contributing factor for poor outcome in RA. Although early therapy has been shown to be particularly effective, there is still uncertainty about the optimal time point of DMARD introduction. A study compared the efficacy of DMARDs in very early RA (median disease duration of 3 months) with that in RA patients with a longer disease duration (12 months) [14]. As early as 3 months after DMARD commencement, there was a significant difference in treatment response in favor of the early treatment, indicating that there is a window of opportunity for optimal therapy. Early diagnosis and therapy appears to be the crucial step in achieving optimal control of RA progression and prognostic improvement [14]. Even patients with undifferentiated arthritis that cannot be classified as RA using current criteria benefit from early MTX treatment [15]. This was shown in the PRObable RA MTX versus Placebo Treatment (PROMPT) study, a double-blind, placebo-controlled, randomized trial involving 110 patients in which MTX reduced the progression rates from undifferentiated arthritis to full-blown RA and retarded radiographic progression [15].
Leflunomide Leflunomide is an oral synthetic DMARD that is rapidly absorbed and metabolized to A771726, its active metabolite [16]. Two mechanisms of action have been identified: inhibition of dihydroorotate dehydrogenase, a key enzyme of the de novo synthesis of pyrimidines, and inhibition of tyrosine kinases [16]. In clinically relevant concentrations, the main mode of action is probably the inhibition of dihydroorotate dehydrogenase. Activated lymphocytes expand their pyrimidine pools 8-fold and need both, de novo synthesis and salvage pathways to cover their pyrimidine requirements [17]. Thus the inhibition of dihydroorotate dehydrogenase by A771726 prevents lymphocytes from accumulating sufficient pyrimidine nucleotides to support DNA synthesis and numerous other metabolic pathways for which pyrimidine ribonucleotides are essential [17]. The biologic effects of leflunomide are manifold and include interference with leukocyte adhesion to endothelial cells, and effects on antigen presentation by dendritic cells, NF-ΚB activation, among many others [17]. Leflunomide is frequently used as a substitute for MTX, when MTX cannot be tolerated. The comparison of the clinical efficacy of leflunomide in RA with that of sulfasalazine suggested superior efficacy [18,19] and similar efficacy to that of MTX [20,21]. Typical side effects of leflunomide consist of diarrhea, reversible alopecia, arterial hypertension [21,22], a slightly elevated incidence of serious infections [23], and liver enzyme elevations similar to MTX. Over 24 months, serious treatment-related adverse events were reported in 1.6% of patients treated with leflunomide and in 3.7% of MTX-treated patients [21]. The observation that MTX at low doses mainly inhibits purine biosynthesis whereas leflunomide inhibits pyrimidine biosynthesis, presents a rationale for their combined treatment [8,17]. Indeed, a 24week, randomized, double-blind, placebo-controlled trial demonstrated that the addition of leflunomide to concomitant stable-dose MTX therapy [24] provided clinical benefit in active RA. The combination of MTX plus leflunomide was generally well tolerated and used safely with liver enzyme and hematologic monitoring [24].
Hydroxychloroquine Antimalarials have a plethora of immunomodulatory effects [25,26]. One of the most important mechanisms of action is related to the signaling of toll-like receptors (TLR) 7 and 9, which are found in lysosomes and normally sense cell free nucleic acids as danger signals. Upon activation, these TLR stimulate a type I interferon response which is particularly characteristic for connective tissue diseases. Antimalarials are weak bases that enter the lysosomes and interfere with functions that require an acidic pH. Antimalarials therefore block the stimulation of TLR 7 and 9 by their ligands. In addition to their immunomodulatory effects, antimalarial agents offer a number of effects of clinical importance [25]. Antimalarials accumulate in high concentration in the epidermis where they absorb ultraviolet light as a trigger of lupus flares [25]. Furthermore, antimalarials have antithrombotic effects and lower the serum cholesterol [25]. Antimalarials are among the safest antirheumatic medications [25,27] and serious side effects are extremely rare. Hydroxychloroquine has a lower risk of retinopathy than chloroquine [28] and therefore preferred in rheumatology practice. Antimalarial agents are of particular importance in the treatment of systemic lupus erythematosus (SLE), in which they improve cutaneous manifestations, arthritis, and constitutional symptoms, prevent disease onset, relapses and organ damage [25,29-31]. There is also evidence that antimalarials decrease the risk of thromboembolic events in SLE and even improve patient survival [25,32,33]. In a case-control study that involved 608 patients, the odds ratio for death among patients treated with hydroxychloroquine was 0.13 [32]. SLE patients who used antimalarial agents for a longer time had lower mortality rates than patients who used them for a shorter time [25,33].
Disclosures None
References (1) Hoes JN, Jacobs JW, Buttgereit F et al. Current view of glucocorticoid co-therapy with DMARDs in rheumatoid arthritis. Nat Rev Rheumatol 2010;6:693-702. (2) Cutolo M, Spies CM, Buttgereit F et al. The supplementary therapeutic DMARD role of lowdose glucocorticoids in rheumatoid arthritis. Arthritis Res Ther 2014;16 Suppl 2:S1. (3) del R, I, Battafarano DF, Restrepo JF et al. Glucocorticoid dose thresholds associated with allcause and cardiovascular mortality in rheumatoid arthritis. Arthritis Rheumatol 2014;66:264272. (4) Cutolo M. Night-time Glucocorticoid – A Paradigm Shift in Glucocorticoid Therapy in Rheumatoid Arthritis? Eur Musculoskel Rev 2009;4:41-43. (5) Arvidson NG, Gudbjornsson B, Larsson A et al. The timing of glucocorticoid administration in rheumatoid arthritis. Ann Rheum Dis 1997;56:27-31. (6) Cutolo M, Straub RH, Buttgereit F. Circadian rhythms of nocturnal hormones in rheumatoid arthritis: translation from bench to bedside. Ann Rheum Dis 2008;67:905-908. (7) Lopez-Olivo MA, Siddhanamatha HR, Shea B et al. Methotrexate for treating rheumatoid arthritis. Cochrane Database Syst Rev 2014;6:CD000957.
(8) Kremer JM. Methotrexate and leflunomide: biochemical basis for combination therapy in the treatment of rheumatoid arthritis. Semin Arthritis Rheum 1999;29:14-26. (9) Choi HK, Hernan MA, Seeger JD et al. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002;359:1173-1177. (10) Wasko MC, Dasgupta A, Hubert H et al. Propensity-adjusted association of methotrexate with overall survival in rheumatoid arthritis. Arthritis Rheum 2013;65:334-342. (11) Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis 2009;68:1094-1099. (12) Schiff MH, Jaffe JS, Freundlich B. Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses >/=15 mg may be overcome with subcutaneous administration. Ann Rheum Dis 2014;73:1549-1551. (13) Braun J, Kastner P, Flaxenberg P et al. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum 2008;58:73-81. (14) Nell VP, Machold KP, Eberl G et al. Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology (Oxford) 2004;43:906-914. (15) van DH, van AJ, Lard LR et al. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2007;56:1424-1432. (16) Fox RI. Mechanism of action of leflunomide in rheumatoid arthritis. [review] [40 refs]. Journal of Rheumatology - Supplement 1998;53:20-26. (17) Breedveld FC, Dayer JM. Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis 2000;59:841-849. (18) Smolen JS, Kalden JR, Scott DL et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group. Lancet 1999;353:259-266. (19) Scott DL, Smolen JS, Kalden JR et al. Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine. Ann Rheum Dis 2001;60:913-923. (20) Strand V, Cohen S, Schiff M et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med 1999;159:2542-2550. (21) Cohen S, Cannon GW, Schiff M et al. Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group. Arthritis Rheum 2001;44:1984-1992. (22) Fleischmann R. Safety and efficacy of disease-modifying antirheumatic agents in rheumatoid arthritis and juvenile rheumatoid arthritis. Expert Opin Drug Saf 2003;2:347-365.
(23) Jenks KA, Stamp LK, O'Donnell JL et al. Leflunomide-associated infections in rheumatoid arthritis. J Rheumatol 2007;34:2201-2203. (24) Kremer JM, Genovese MC, Cannon GW et al. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, doubleblind, placebo-controlled trial. Ann Intern Med 2002;137:726-733. (25) Wallace DJ, Gudsoorkar VS, Weisman MH et al. New insights into mechanisms of therapeutic effects of antimalarial agents in SLE. Nat Rev Rheumatol 2012;8:522-533. (26) Venuturupalli S, Gudsoorkar V, Wallace D. Reconsidering antimalarials in systemic lupus erythematosus: developments of translational clinical interest. J Rheumatol 2012;39:17691771. (27) Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses. Arthritis Rheum 1990;33:14491461. (28) Block JA. Hydroxychloroquine and retinal safety. Lancet 1998;351:771. (29) Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P et al. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 2010;69:20-28. (30) A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. N Engl J Med 1991;324:150154. (31) Pons-Estel GJ, Alarcon GS, McGwin G, Jr. et al. Protective effect of hydroxychloroquine on renal damage in patients with lupus nephritis: LXV, data from a multiethnic US cohort. Arthritis Rheum 2009;61:830-839. (32) Alarcon GS, McGwin G, Bertoli AM et al. Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L). Ann Rheum Dis 2007;66:1168-1172. (33) Shinjo SK, Bonfa E, Wojdyla D et al. Antimalarial treatment may have a time-dependent effect on lupus survival: data from a multinational Latin American inception cohort. Arthritis Rheum 2010;62:855-862.
PII: DOI: Reference:
S0037-1963(16)30029-4 http://dx.doi.org/10.1053/j.seminhematol.2016.04.017 YSHEM50873
To appear in: Seminars in Hematology Cite this article as: Ulrich A. Walker, Immunomodulation of rheumatologic disorders with non-biologic disease modifying antirheumtic drugs, Seminars in Hematology, http://dx.doi.org/10.1053/j.seminhematol.2016.04.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Immunomodulation of rheumatologic disorders with non-biologic disease modifying antirheumtic drugs
Ulrich A. Walker Unispital Basel Dept. of Rheumatology Petersgraben 4 CH 4037 Basel Switzerland Tel.:
+41-61-2652525
Fax:
+41-61-2659021
E-Mail: [email protected]
Keywords: Antirheumatic agents, treatment outcome, mode of action
Abstract Although biological agents have revolutionized the immunomodulation of many rheumatic disorders, conventional disease modifying antirheumatic drugs (DMARDs) remain important glucocorticosteroid sparing agents and combination partners. In rheumatoid arthritis, low-dose glucocorticosteroids can be regarded as a DMARD due to preventive effects on joint erosions. Therapy with methothrexate and possibly also other DMARDs may alter the natural evolution of rheumatoid arthritis severity over time and therapy should be instituted as early as possible. Leflunomide is an equipotent alternative to methotrexate in rheumatoid arthritis, if methotrexate cannot be tolerated. Hydroxychloroquine inhibits toll-like receptor signaling and exerts antithrombotic and antihyperlipidemic effects, all thought to be beneficial in systemic lupus erythematosus. Hydroxychloroquine improves organ involvement in lupus, prevents lupus flares and reduces mortality. It should be given to every lupus patient without contraindications.
Introduction The management of rheumatoid arthritis (RA) and many other autoimmune diseases (AIDs) is frequently based on the use of glucocorticosteroids (GC) and disease-modifying antirheumatic drugs (DMARDs), with the latter being administered either as synthetic compounds, or as biological agents. GC are mostly used for the treatment initiation, as the onset of their effect is relatively rapid. The therapeutic onset of most DMARDs in contrast is frequently prolonged and may even take weeks [1]. Adding synthetic or biologic DMARDs to GC, or replacing GC treatment with DMARDs is common clinical practice in many AIDs in order to prevent or diminish GC side effects. Although biological agents have revolutionized the treatment of many rheumatic disorders, conventional DMARDs remain important anchor drugs in the therapeutic armamentarium and are mostly used as first-line GC-sparing agents prior to the use of biological agents. This article provides an overview of the most important conventional DMARDs.
Glucocorticosteroids GC treatment remain an important pillar in the treatment of RA not only due to their rapid onset of action, but also because of clear evidence that initial low-dose GC treatment slows the radiographic progression of the disease [2]. Low-dose initial GC treatment favorably alter the disease course for years, and this effect persists even after complete GC discontinuation [1]. Thus GC satisfy the conventional definition of a DMARD [2]. Long-term high-dose GC therapy is however associated with inevitable side effects. Continued GC exposure is even associated with a dose-dependent increase in all-cause mortality and also with cardiovascular death, as shown in RA [3]. The prednisone dose threshold associated with an increase in mortality was 8-15 mg per day, with an adjusted hazard ratio of 1.78 compared to RA patients without GC treatment [3]. For the cumulative GC dose, the minimum dosage associated with an increase in all-cause mortality was 40 grams [3]. In RA, interleukin-6 and other pro-inflammatory cytokines are detectable in high amounts in the early morning hour serum. The cytokine levels correlate with morning stiffness and other markers of RA activity [4]. The circadian increase of endogenous cortisol in the early morning hours however lags the increase of cytokines by 1-2 hours [4]. This observation and the fact that low dose prednisone is more effective when given at night compared to morning doses [5] have led to the development of an oral slow-release prednisone tablet. This formulation is taken at bedtime, releases prednisone at about 2am and efficiently counteracts the peak of proinflammatory cytokines in the early morning serum. Compared to conventional morning GC doses, the slow-release GC formulation enhances the control of morning stiffness and possibly also other measures of RA activity [4,6].
Methotrexate Methotrexate (MTX) binds to dihydrofolate reductase an enzyme necessary for the de novo synthesis of purine and pyrimidine nucleotides and for the maintenance of many other metabolic pathways [7]. In the low doses used in rheumatology, MTX inhibits mainly the purine biosynthesis [8]. MTX monotherapy shows a clinically important and statistically significant control of RA activity when compared with placebo, improves physical function, and counteracts radiographic progression [7]. Remission rates are however low when MTX is given alone [7]. Patients who do not respond to MTX alone typically improve with combinations of MTX and other DMARDs. Patients receiving MTX monotherapy are twice as likely to discontinue treatment due to adverse events compared to placebo (16% versus 8%), but have no differences in the total number of serious adverse events [7]. Several studies have suggested that MTX provides a substantial survival benefit in patients with RA [9,10]. The optimal dose for MTX is debated for a long time. Multinational recommendations for its use recommend that MTX should be started orally at 10–15 mg/week, with escalation of 5 mg every 2–4
weeks up to 20–30 mg/week, depending on the clinical response and tolerability [11]. One more recent study directly compared the relative bioavailability, safety and tolerability of oral MTX and subcutaneous MTX in patients with RA [12]. Systemic exposure of oral MTX plateaued at doses beyond 15 mg/week. Subcutaneous MTX in contrast demonstrated a linear increase in systemic exposure with serum levels greater than those of oral MTX dosing, particularly beyond 15 mg/week. Thus, patients with an inadequate clinical response to oral MTX may benefit from higher drug exposure by switching to subcutaneous MTX. A randomized blinded, placebo controlled comparison found that subcutaneous administration of MTX was significantly more effective in RA than oral MTX dosing [13]. Multinational recommendations recommend parenteral administration of MTX in the case of inadequate clinical response or intolerance to prior oral doses [11]. Delay of DMARD therapy is a major contributing factor for poor outcome in RA. Although early therapy has been shown to be particularly effective, there is still uncertainty about the optimal time point of DMARD introduction. A study compared the efficacy of DMARDs in very early RA (median disease duration of 3 months) with that in RA patients with a longer disease duration (12 months) [14]. As early as 3 months after DMARD commencement, there was a significant difference in treatment response in favor of the early treatment, indicating that there is a window of opportunity for optimal therapy. Early diagnosis and therapy appears to be the crucial step in achieving optimal control of RA progression and prognostic improvement [14]. Even patients with undifferentiated arthritis that cannot be classified as RA using current criteria benefit from early MTX treatment [15]. This was shown in the PRObable RA MTX versus Placebo Treatment (PROMPT) study, a double-blind, placebo-controlled, randomized trial involving 110 patients in which MTX reduced the progression rates from undifferentiated arthritis to full-blown RA and retarded radiographic progression [15].
Leflunomide Leflunomide is an oral synthetic DMARD that is rapidly absorbed and metabolized to A771726, its active metabolite [16]. Two mechanisms of action have been identified: inhibition of dihydroorotate dehydrogenase, a key enzyme of the de novo synthesis of pyrimidines, and inhibition of tyrosine kinases [16]. In clinically relevant concentrations, the main mode of action is probably the inhibition of dihydroorotate dehydrogenase. Activated lymphocytes expand their pyrimidine pools 8-fold and need both, de novo synthesis and salvage pathways to cover their pyrimidine requirements [17]. Thus the inhibition of dihydroorotate dehydrogenase by A771726 prevents lymphocytes from accumulating sufficient pyrimidine nucleotides to support DNA synthesis and numerous other metabolic pathways for which pyrimidine ribonucleotides are essential [17]. The biologic effects of leflunomide are manifold and include interference with leukocyte adhesion to endothelial cells, and effects on antigen presentation by dendritic cells, NF-ΚB activation, among many others [17]. Leflunomide is frequently used as a substitute for MTX, when MTX cannot be tolerated. The comparison of the clinical efficacy of leflunomide in RA with that of sulfasalazine suggested superior efficacy [18,19] and similar efficacy to that of MTX [20,21]. Typical side effects of leflunomide consist of diarrhea, reversible alopecia, arterial hypertension [21,22], a slightly elevated incidence of serious infections [23], and liver enzyme elevations similar to MTX. Over 24 months, serious treatment-related adverse events were reported in 1.6% of patients treated with leflunomide and in 3.7% of MTX-treated patients [21]. The observation that MTX at low doses mainly inhibits purine biosynthesis whereas leflunomide inhibits pyrimidine biosynthesis, presents a rationale for their combined treatment [8,17]. Indeed, a 24week, randomized, double-blind, placebo-controlled trial demonstrated that the addition of leflunomide to concomitant stable-dose MTX therapy [24] provided clinical benefit in active RA. The combination of MTX plus leflunomide was generally well tolerated and used safely with liver enzyme and hematologic monitoring [24].
Hydroxychloroquine Antimalarials have a plethora of immunomodulatory effects [25,26]. One of the most important mechanisms of action is related to the signaling of toll-like receptors (TLR) 7 and 9, which are found in lysosomes and normally sense cell free nucleic acids as danger signals. Upon activation, these TLR stimulate a type I interferon response which is particularly characteristic for connective tissue diseases. Antimalarials are weak bases that enter the lysosomes and interfere with functions that require an acidic pH. Antimalarials therefore block the stimulation of TLR 7 and 9 by their ligands. In addition to their immunomodulatory effects, antimalarial agents offer a number of effects of clinical importance [25]. Antimalarials accumulate in high concentration in the epidermis where they absorb ultraviolet light as a trigger of lupus flares [25]. Furthermore, antimalarials have antithrombotic effects and lower the serum cholesterol [25]. Antimalarials are among the safest antirheumatic medications [25,27] and serious side effects are extremely rare. Hydroxychloroquine has a lower risk of retinopathy than chloroquine [28] and therefore preferred in rheumatology practice. Antimalarial agents are of particular importance in the treatment of systemic lupus erythematosus (SLE), in which they improve cutaneous manifestations, arthritis, and constitutional symptoms, prevent disease onset, relapses and organ damage [25,29-31]. There is also evidence that antimalarials decrease the risk of thromboembolic events in SLE and even improve patient survival [25,32,33]. In a case-control study that involved 608 patients, the odds ratio for death among patients treated with hydroxychloroquine was 0.13 [32]. SLE patients who used antimalarial agents for a longer time had lower mortality rates than patients who used them for a shorter time [25,33].
Disclosures None
References (1) Hoes JN, Jacobs JW, Buttgereit F et al. Current view of glucocorticoid co-therapy with DMARDs in rheumatoid arthritis. Nat Rev Rheumatol 2010;6:693-702. (2) Cutolo M, Spies CM, Buttgereit F et al. The supplementary therapeutic DMARD role of lowdose glucocorticoids in rheumatoid arthritis. Arthritis Res Ther 2014;16 Suppl 2:S1. (3) del R, I, Battafarano DF, Restrepo JF et al. Glucocorticoid dose thresholds associated with allcause and cardiovascular mortality in rheumatoid arthritis. Arthritis Rheumatol 2014;66:264272. (4) Cutolo M. Night-time Glucocorticoid – A Paradigm Shift in Glucocorticoid Therapy in Rheumatoid Arthritis? Eur Musculoskel Rev 2009;4:41-43. (5) Arvidson NG, Gudbjornsson B, Larsson A et al. The timing of glucocorticoid administration in rheumatoid arthritis. Ann Rheum Dis 1997;56:27-31. (6) Cutolo M, Straub RH, Buttgereit F. Circadian rhythms of nocturnal hormones in rheumatoid arthritis: translation from bench to bedside. Ann Rheum Dis 2008;67:905-908. (7) Lopez-Olivo MA, Siddhanamatha HR, Shea B et al. Methotrexate for treating rheumatoid arthritis. Cochrane Database Syst Rev 2014;6:CD000957.
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