Pharmacoeconomics.
2005;23(4):395-420.
Modelling Cost Effectiveness and Cost Utility of Sequential DMARD
Therapy Including Leflunomide for Rheumatoid Arthritis in Germany : II.
The Contribution of Leflunomide to Efficiency.
Schadlich PK, Zeidler H, Zink A, Gromnica-Ihle E, Schneider M,
Straub C, Brecht JG, Huppertz E.
InForMed GmbH, Outcomes Research and Health Economics, Ingolstadt,
Germany.
OBJECTIVE: To estimate the 3-year incremental cost effectiveness and
cost utility of introducing leflunomide into sequential therapy, consisting
of the most frequently used disease-modifying antirheumatic drugs (DMARDs),
for patients with rheumatoid arthritis in specialised, i.e. rheumatological,
care in Germany. DESIGN AND SETTING: The analysis was conducted from the
societal perspective in Germany using an existing 3-year simulation model,
which was adapted to the German healthcare system after secondary analysis
of relevant publications and data. DMARD sequences including leflunomide
were compared with those excluding leflunomide. Costs comprised direct
costs incurred by treatment and indirect costs incurred by loss of productivity
(sick leave and premature retirement) of rheumatoid arthritis patients.
Effectiveness parameters were given by response years gained (RYGs) according
to the American College of Rheumatology (ACR) criteria for 20%, 50% and
70% improvement (ACR20/50/70RYGs) and by QALYs gained (QALYGs). Costs,
effects and QALYs were discounted by 5% per annum. In the base-case analysis,
average values of costs, response years and QALYs were applied. Costs
were in 1998-2001 values (euro1 approximate, equals $US0.91, average of
the period from the year 2000 through 2001). MAIN OUTCOME MEASURES AND
RESULTS: After 3 years, adding leflunomide was less costly and more effective
than the strategy excluding leflunomide when total (direct and indirect)
costs were considered. There were savings of euro271 777 and 8.1, 4.3,
5.1 and 4.9 ACR20RYGs, ACR50RYGs, ACR70RYGs and QALYGs per 100 patients,
respectively, obtained through adding leflunomide. Focusing on direct
costs, adding leflunomide was more costly and more effective compared
with excluding leflunomide, with an incremental cost effectiveness of
euro5004 per ACR20RYG, euro9535 per ACR50RYG, euro7996 per ACR70RYG, and
an incremental cost utility of euro8301 per QALYG, after 3 years. The
robustness of the results was shown in comprehensive sensitivity analyses.
In the analysis of extremes, different combinations of the limits of cost,
effectiveness and utility parameters were investigated. Adding leflunomide
to sequential DMARD therapy remained dominant in 79% of the possible cases,
i.e. was less costly and more effective than the strategy excluding leflunomide.
Focusing on direct costs, adding leflunomide became dominant in 29% and
remained more costly and more effective in 50% of possible cases. CONCLUSIONS:
Our analysis suggests, with its underlying data and assumptions, that
having leflunomide as an additional option in a DMARD treatment sequence
extends the time patients benefit from DMARD therapy at reasonable additional
direct costs. Adding leflunomide may even be cost saving when total (direct
and indirect) costs are considered. As data on DMARD effectiveness were
extracted from the results of clinical trials, real-world data from observational
studies would be needed to corroborate the findings of the present analysis.
N Engl J Med. 2005 Apr 21;352(16):1655-66.
Leflunomide or methotrexate for juvenile rheumatoid arthritis.
Silverman E, Mouy R, Spiegel L, Jung LK, Saurenmann RK, Lahdenne
P, Horneff G, Calvo I, Szer IS, Simpson K, Stewart JA, Strand V; Leflunomide
in Juvenile Rheumatoid Arthritis (JRA) Investigator Group.
Department of Pediatrics, University of Toronto, Toronto. esilverman@sickkids.ca
BACKGROUND: We compared the safety and efficacy of leflunomide with that
of methotrexate in the treatment of polyarticular juvenile rheumatoid
arthritis in a multinational, randomized, controlled trial. METHODS: Patients
3 to 17 years of age received leflunomide or methotrexate for 16 weeks
in a double-dummy, blinded fashion, followed by a 32-week blinded extension.
The rates of American College of Rheumatology Pediatric 30 percent responses
(ACR Pedi 30) and the Percent Improvement Index were assessed at baseline
and every 4 weeks for 16 weeks and every 8 weeks during the 32-week extension
study. RESULTS: Of 94 patients randomized, 86 completed 16 weeks of treatment,
70 of whom entered the extension study. At week 16, more patients in the
methotrexate group than in the leflunomide group had an ACR Pedi 30 response
(89 percent vs. 68 percent, P=0.02), whereas the values for the Percent
Improvement Index did not differ significantly (-52.87 percent vs. -44.41
percent, P=0.18). In both groups, the improvements achieved at week 16
were maintained at week 48. The most common adverse events in both groups
included gastrointestinal symptoms, headache, and nasopharyngeal symptoms.
Aminotransferase elevations were more frequent with methotrexate than
with leflunomide during the initial study and the extension study. CONCLUSIONS:
In patients with polyarticular juvenile rheumatoid arthritis, methotrexate
and leflunomide both resulted in high rates of clinical improvement, but
the rate was slightly greater for methotrexate. At the doses used in this
study, methotrexate was more effective than leflunomide. Copyright 2005
Massachusetts Medical Society.
Int Immunopharmacol. 2005 Jun;5(6):1085-90. Epub 2004 Dec 15.
Leflunomide reduces nitric oxide production in patients with
active rheumatoid arthritis.
Reddy SV, Wanchu A, Khullar M, Govindrajan S, Bambery P.
Department of Internal Medicine, Postgraduate Institute of Medical
Education and Research, Chandigarh 160012, India.
OBJECTIVES: Leflunomide is an immunomodulatory agent that was recently
approved for the treatment of rheumatoid arthritis (RA). The mechanism
of action is not fully understood. Nitric oxide (NO) plays an important
role in the pathogenesis of RA. Leflunomide has been shown to cause cell
specific inhibition of inducible nitric oxide synthase (iNOS) activation
in animal models. We carried out this study to determine if there was
alteration in NO production in patients with RA. METHODS: An 8-week open
label study was carried out on patients with adult onset active RA. We
measured levels of nitrite and citrulline spectrophotometrically as surrogate
markers of NO production. Within-patient serum levels of nitrite and citrulline
were compared with leflunomide therapy at three points of time (at 0,
4 and 8 weeks of therapy). RESULTS: Thirty-three patients with active
RA were enrolled for this study. These patients were a subset of 63 individuals
who are studied for clinical efficacy of leflunomide. Three patients were
lost to follow-up. Median nitrite levels were 817.2 (nmol/ml) at the start
of therapy and this declined to 440.9 nmol/ml and 301.1 nmol/ml at 4 and
8 weeks of therapy. Median citrulline levels were 649.3 nmol/ml at the
start of the study, which declined to 549.2 nmol/ml and 485.4 nmol/ml
at 4 and 8 weeks, respectively. Statistically significant decrease in
median values for serum nitrite and citrulline levels was documented after
4 weeks of leflunomide therapy (p<0.01), which was sustained at 8 weeks
(p<0.01), although there was no further fall between 4 and 8 weeks
(p>0.1). CONCLUSIONS: Leflunomide inhibits nitric oxide production
in patients with active RA. Inhibition of NO synthesis may be one of the
mechanisms responsible for the immunomodulatory activity of leflunomide.
J Eur Acad Dermatol Venereol. 2005 Mar;19(2):243-6.
Successful treatment of a leg ulcer occurring in a rheumatoid
arthritis patient under leflunomide therapy.
Knab J, Goos M, Dissemond J.
Department of Dermatology, University of Essen, Germany.
ABSTRACT Objective We report the case of a leg ulcer in a rheumatoid
arthritis (RA) patient under treatment with leflunomide, discuss the influence
of the drug on the aetiopathogenesis of the ulcer and describe its successful
treatment. Case summary A 68-year-old woman with a 12-year history of
RA developed a leg ulcer after 4 months of leflunomide treatment. Other
ulcerogenic factors were ruled out. There were some clinical hints for
rheumatoid vasculitis. The ulcer was resistant to ambulant conservative
phase adapted wound bed preparation and a split skin transplantation failed.
After omission of leflunomide and washout procedure with cholestyramine
a second split skin transplantation resulted in complete healing. Discussion
Leflunomide inhibits the division of activated T cells and thus inhibits
among others the production of proinflammatory cytokines and the adhesion
of cells to the endothelium. These mechanisms may partly explain the possible
influence of leflunomide on the perpetuation of the ulcer. Until now,
occurrence of vasculitis and leg ulcers has been described in one case
each for the novel immunomodulator leflunomide. No successful treatment
of a leg ulcer under leflunomide has been described yet. Omission of leflunomide
and a washout treatment in our case led to a complete healing. This may
indicate a critical role of leflunomide in the maintenance of this slow
healing ulcer. Conclusions An association between leflunomide intake,
occurrence of leg ulcers in RA patients and delayed wound healing should
be considered.
Transplantation. 2005 Jan 15;79(1):116-8.
Effect of leflunomide and cidofovir on replication of BK virus
in an in vitro culture system.
Farasati NA, Shapiro R, Vats A, Randhawa P.
Department of Pathology, University of Pittsburgh Medical Center,
Pittsburgh, PA 15213, USA.
BACKGROUND: Cidofovir and Leflunomide are used empirically in the treatment of BK virus nephropathy. The aim of this study is to quantify the antiviral activity of these drugs. METHODS: BK virus was grown in a cell-culture system. The rate of viral replication in the presence or absence of the drug being tested was assessed using a quantitative polymerase chain reaction assay. RESULTS: The inhibitory concentration, effective concentration, and selectivity index for Leflunomide are 39.7+/-6.9, 11.3+/-2.8, and 3.8+/-0.8 microg/mL, respectively. For Cidofovir, these indices were, respectively, 63.9+/-17.2, 36.3+/-11.7, and 2.3+/-0.8 microg/mL. CONCLUSIONS: The in vitro activity of Cidofovir and Leflunomide is modest, and the selectivity index is low. There is a need to develop more effective and less toxic anti-BK virus drugs for clinical use.
Transplantation. 2005 Jan 27;79(2):135-41; discussion 133-4.
Effects of a short course of leflunomide on T-independent B-lymphocyte
xenoreactivity and on susceptibility of xenografts to acute or chronic
rejection.
Yan Y, Verbeken E, Yu L, Rutgeerts O, Goebels J, Segers C, Lin Y, Waer
M.
Laboratory for Experimental Transplantation, University of Leuven,
Herestraat 49, Leuven, B-3000, Belgium.
BACKGROUND: Leflunomide is a novel immunosuppressive agent with promising
activity for xenotransplantation. It is not clear yet which mechanisms
of action of leflunomide are responsible for that. METHODS: In a hamster-to-C57BL/6
nude mouse heart transplantation model, a 2-week course of leflunomide
was used after transplantation or for pretreating donors. Nontolerant
B lymphocytes were transferred to recipients after transplantation of
first or second xenogeneic heart grafts that were transplanted with or
without leflunomide treatment. RESULTS: Hamster xenogeneic hearts transplanted
into athymic C57BL/6 nude mice receiving leflunomide did not induce immunoglobulin
(Ig) M xenoantibodies (XAb) and survived without signs of chronic rejection.
Second xenogeneic hearts transplanted 4 weeks after withdrawal of leflunomide
survived without induction of XAb but developed chronic vascular lesions.
After injection of naive B lymphocytes at 6 weeks after grafting a first
or second hamster heart, only in the latter case were XAb induced. These
were deposited in, and provoked acute rejection of, only the second grafts.
Pretreatment of donors with leflunomide decreased the ex vivo xenoantibody
deposition on the xenogeneic heart endothelia. CONCLUSIONS: A short posttransplant
course of leflunomide induces T-independent B-lymphocyte xenotolerance.
Leflunomide treatment also influences xenoantigen expression, as nontolerant
B lymphocytes provoke IgM XAb formation and rejection of only second xenografts
(transplanted without leflunomide) and not of first xenografts (transplanted
with leflunomide treatment). The ex vivo experiments that show that XAb
deposition is decreased in leflunomide-pretreated xenografts further confirm
this. The latter may also explain the resistance of first and not second
xenografts against chronic rejection.
Cancer. 2004 Oct 1;101(7):1569-74.
Rosiglitazone versus placebo for men with prostate carcinoma and
a rising serum prostate-specific antigen level after radical prostatectomy
and/or radiation therapy.
Smith MR, Manola J, Kaufman DS, George D, Oh WK, Mueller E, Slovin
S, Spiegelman B, Small E, Kantoff PW.
Division of Hematology and Medical Oncology, Massachusetts General
Hospital, Boston 02114, USA. smith.matthew@mgh.harvard.edu
BACKGROUND: The objective of this study was to assess the biologic activity of rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist that has been approved to treat type 2 diabetes, in men with recurrent prostate carcinoma using change in prostate specific antigen (PSA) doubling time (PSADT) as the primary outcome variable. METHODS: Men with histologically confirmed prostate carcinoma, no recent hormone therapy, a rising serum PSA level after radical prostatectomy and/or radiation therapy, and no radiographic evidence of metastases were assigned randomly to receive either oral rosiglitazone (4 mg twice daily) or placebo. The treatment was continued until the men developed disease progression or adverse effects. A positive outcome was defined as a posttreatment PSADT > 150% the baseline PSADT and no new metastases. RESULTS: One hundred six men were enrolled. The median treatment duration was 315 days for men in the placebo group and 338 days for men in the rosiglitazone group (P = 0.28). Forty percent of men in the in the placebo group and 38% of men in the rosiglitazone group had a posttreatment PSADT > 150% of the baseline PSADT and no new metastases (P = 1.00). In exploratory analyses, the rate of a positive outcome remained higher than expected in the placebo group, even when a positive outcome was redefined using more stringent criteria. The time to disease progression was similar between the groups. CONCLUSIONS: Rosiglitazone did not increase PSADT or prolong the time to disease progression more than placebo in men with a rising PSA level after radical prostatectomy and/or radiation therapy. The unexpected discordance between baseline and posttreatment PSADT in the placebo group reinforced the importance of randomized controlled trials in this setting. (c) 2004 American Cancer Society.
Best Pract Res Clin Rheumatol. 2004 Aug;18(4):507-38.
The treatment of rheumatoid arthritis.
Simon LS.
Beth Israel Deaconess Medical Center, Harvard Medical School, 110
Francis St Suite 4B, Boston, MA 02215, USA. lsimon@bidmc.harvard.edu
The treatment of rheumatoid arthritis has changed dramatically in the last 10 years and in parallel the definition and expectations of patients and clinicians of the effects of disease-modifying anti-rheumatic agents has changed as well. Current expectations of efficacy now include improvement of signs and symptoms of disease activity as well as slowing, if not complete inhibition, of disease progression as measured by X-ray progression along with significant improvement in patient physical function. In addition, clinicians assess the safety profile of these agents more critically in an attempt to improve the risk:benefit profile. Drugs, such as methotrexate, sulfasalazine and leflunomide have provided patients with substantial relief of symptoms and improvement in terms of X-ray progression, but they have been hampered by the occurrence of significant adverse events along with the inability to maintain benefit for prolonged periods of time. With the increased understanding of the basic biological mechanisms of the disease process, there has been the introduction of four biological disease modifying therapies and other drugs into clinical practice, which have altered aspects of the risk:benefit ratio for patients with various rheumatic diseases.
Clin Exp Rheumatol. 2004 Sep-Oct;22(5 Suppl 35):S95-100
Benefit/risk of leflunomide in rheumatoid arthritis.
Kremer JM, Cannon GW.
The Center for Rheumatology, Clinical Professor of Medicine, Albany
Medical College, Albany, New York 12206, USA.
Leflunomide was first shown to have disease-modifying properties in a rat model of adjuvant-induced arthritis. Leflunomide has been subsequently used with success in several animal models of tissue and organ allograft and of autoimmune disease including collagen- and adjuvant-induced arthritis, interstitial nephritis, myasthenia gravis, and systemic lupus erythematosus. Based on its success as an immunosuppressive agent in these models, leflunomide was tested for the treatment of rheumatoid arthritis (RA).
Ann Rheum Dis. 2004 Dec;63(12):1632-7.
Leflunomide inhibits transendothelial migration of peripheral
blood mononuclear cells.
Grisar J, Aringer M, Koller MD, Stummvoll GH, Eselbock D, Zwolfer
B, Steiner CW, Zierhut B, Wagner L, Pietschmann P, Smolen JS.
Division of Rheumatology, Department of Internal Medicine III, Medical
University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
OBJECTIVES: To test whether the active metabolite of leflunomide (LEF-M), in addition to blocking the proliferation of activated lymphocytes by inhibiting dihydro-orotate dehydrogenase (DHODH), influences the transendothelial migration (TEM) of peripheral blood mononuclear cells (PBMC). METHODS: In an in vitro model of PBMC transmigration through an endothelial cell (EC) barrier, PBMC were re-collected in three groups: cells not adherent to the EC, cells bound to, and cells which had migrated through, the EC layer. Experiments in which cells were pretreated with LEF-M (in the absence or in the presence of uridine) were compared with parallel experiments in the presence of medium alone. RESULTS: Preincubation of EC with LEF-M led to a 36 (SEM 16)% reduction in PBMC TEM (p<0.05). Likewise, preincubation of PBMC induced a reduction in their TEM of 39 (9)% (p<0.005). Incubation of both PBMC and EC with LEF-M had an additive effect (mean reduction of 48 (6)%, p<0.005). Incubation of PBMC with LEF-M also decreased monocytic CD44 expression (p<0.005) and PBMC-hyaluronan binding (p<0.05). Incubation of cells with LEF-M and uridine in addition to LEF-M reversed the inhibition of migration, suggesting that the observed effects were due to DHODH inhibition. Fluorocytometric analysis of PBMC subsets within the migrated population showed a decrease of monocytes, but not of B or T cells, after LEF-M treatment. CONCLUSIONS: LEF-M reduces monocytic adhesion molecule expression and TEM and may thus interfere with monocyte and EC activities in RA. Thus, the clinical effects of leflunomide may, at least in part, be due to blocking cell traffic into the inflamed synovia.
Hepatology. 2004 Nov;40(5):1160-9.
Leflunomide protects from T-cell-mediated liver injury in mice
through inhibition of nuclear factor kappaB.
Imose M, Nagaki M, Kimura K, Takai S, Imao M, Naiki T, Osawa
Y, Asano T, Hayashi H, Moriwaki H.
First Department of Internal Medicine, Gifu University School of Medicine,
Gifu, Japan.
Leflunomide is a novel immunosuppressive and anti-inflammatory agent for the treatment of autoimmune disease. The aim of this study was to investigate whether leflunomide protects from liver injury induced by concanavalin A (Con A), a T-cell-dependent model of liver damage. BALB/c mice were injected with 25 mg/kg Con A in the presence or absence of 30 mg/kg leflunomide. Liver injury was assessed biochemically and histologically. Levels of circulating cytokines and expressions of cytokine messenger RNA (mRNA) in the liver and the spleen were determined. Treatment with leflunomide markedly reduced serum transaminase activities and the numbers of dead liver cells. Leflunomide significantly inhibited increases in plasma tumor necrosis factor alpha (TNF-alpha) and interleukin 2 concentrations, and also reduced TNF-alpha mRNA expression in the liver after administration of Con A. These findings were supported by the results in which leflunomide administration decreased the number of T lymphocytes infiltrating the liver as well as inhibiting their production of TNF-alpha. Activation of nuclear factor kappaB (NF-kappaB), which regulates TNF-alpha production, was inhibited in the liver of mice treated with leflunomide, resulting in a reduction of TNF-alpha production from lymphocytes infiltrating the liver. In conclusion, leflunomide is capable of regulating T-cell-mediated liver injury in vivo and that this event may depend on the decrease of TNF-alpha production in the liver through inhibition of NF-kappaB activation caused by leflunomide.
Folia Med (Plovdiv). 2003;45(3):43-7.
Leflunomide in the treatment of refractory rheumatoid arthritis.
Kuzmanova SI, Solakov PT, Batalov AZ, Staikova ND, Andreev SA,
Russafov PB.
Clinic of Rheumatology, Medical University, Plovdiv, Bulgaria.
Leflunomide (LFL) is a modern immunomodulating medication belonging to the group of drugs that favourably affect the course of rheumatoid arthritis (RA). We present in this study the results of an open prospective trial on the effectiveness and side effects of LFL in clinically followed up patients with active RA refractory to other disease modifying anti-rheumatic drugs (DMARDS). At the onset of treatment with LFL the patients had at least 8 swollen and tender joints, the disease severity being assessed by both patients and physicians as over 3 cm VAS. ESR was higher than 40mm/lh. In all patients previous treatment with disease modifying drugs received for at least 3 months was insufficiently effective. It was discontinued prior to the therapy with LFL. Assessment of the therapeutic results was made at 3, 6 and 12 months after onset of LFL therapy. The following parameters were followed-up: 1) Number of tender joints, 2) Number of swollen joints, 3) Morning stiffness (min), 4) Global assessment of the patient (VAS 1-10 cm), 5) Global assessment of the physician (VAS 1-10 cm); 6) ESR - mm/lh; 7) Mean HAQ - the sum of all scores (0-3), divided by the number of the questions5; 8) SDAI index of RA activity6; 9) ACR20% and ACR50% positive therapeutic effect2. RESULTS: 82 patients (mean age 53.9 yrs, age range 20-70, 12 males, 70 females) were studied. RA was diagnosed in 80 (97.6%); RA combined with spondyloarthritis was diagnosed in 2 patients (2.4%). The mean duration of RA was 5.1 +/- 3.4 yrs. 70 patients (85.4%) were rheumatoid factor positive. The therapeutic effect from the administration of LFL was markedly good as early as at 3 months from beginning of treatment and was sustained significantly favourable at 12 months. The therapeutic effect of LFL referring to ACR20% is high - 36% at 3 months from onset of therapy and increased to 51% at 12 months. A grave side effect - leucopenia with granulocytopenia was observed in one female patient. LFL is a novel effective disease-modifying drug used to treat refractory RA. In a short term period - 3 to 6 months, LFL leads to a significant clinical and functional improvement of the patients.
Br J Clin Pharmacol. 2004 Aug;58(2):201-8.
Leflunomide in active rheumatoid arthritis: a prospective study
in daily practice.
Van Roon EN, Jansen TL, Mourad L, Houtman PM, Bruyn GA, Griep
EN, Wilffert B, Tobi H, Brouwers JR.
Department of Hospital Pharmacy and Clinical Pharmacology, Medical
Centre Leeuwarden, Leeuwarden, The Netherlands. E.N.van.Roon@ZNB.nl
AIMS: We prospectively studied the efficacy, incidence of adverse drug reactions and withdrawal from leflunomide in an outpatient population with rheumatoid arthritis in a setting of care-as-usual. METHODS: In this prospective case series study, a standard dataset was collected from outpatient medical records, including patient and disease characteristics, data on leflunomide use and adverse drug reactions. RESULTS: During the study period 136 rheumatoid arthritis patients started leflunomide. Median (range) follow-up duration was 317 (11-911) days. Sixty-five percent of patients experienced at least one adverse drug reaction related to leflunomide. During follow-up 76 patients (56%) withdrew from leflunomide treatment, mainly because of adverse drug reactions (29%) or lack of efficacy (13%). The overall incidence density for withdrawal from leflunomide was 56.2 per 100 patient years. Complete data for calculating efficacy using a validated disease activity score on 28 joints (DAS(28)) was available for 48, 36, and 35% of patients at 2, 6, and 12 months follow-up, respectively. Within a 12-month period after start of leflunomide treatment 76% of the evaluable patients were classified as moderate or good responders according to the DAS(28) response criteria. CONCLUSIONS: In the setting of care-as-usual rheumatoid arthritis patients starting leflunomide frequently experienced adverse drug reactions. More than half of the patients withdrew from leflunomide treatment within 1 year of starting leflunomide treatment, mainly because of adverse drug reactions.
Br J Dermatol. 2004 Jun;150(6):1182-5.
Leflunomide as a novel treatment option in severe atopic dermatitis.
Schmitt J, Wozel G, Pfeiffer C.
Department of Dermatology, Medical Faculty Carl Gustav Carus, Technical
University Dresden, 01307, Germany.
BACKGROUND: Based on the increasing knowledge of T-cell-mediated pathogenesis in atopic dermatitis (AD), systemic immunosuppressive drugs are increasingly applied. The chronic, relapsing course of severe AD necessitates a drug, both efficacious and safe in long-term application. Leflunomide is a pyrimidine de novo synthesis-inhibiting immunosuppressant exhibiting an extremely long in vivo half life of its active metabolite. OBJECTIVES: To evaluate the efficacy of leflunomide in long-term treatment of AD. METHODS: As a proof of principle, we treated two patients with severe AD, recalcitrant to different systemic treatment modalities, for 20 months with leflunomide (loading dose 100 mg daily during 3 days; maintenance dose 20 mg daily). At regular visits physical examination, eczema area and severity index (EASI), visual analogue scale (VAS) for itching, and laboratory findings were assessed with according adjustment of the leflunomide dose. RESULTS: At the initiation of leflunomide therapy, both patients presented with almost erythrodermic AD (patient 1, EASI 40.0, VAS 10; patient 2, EASI 43.0, VAS 8). Partial remission was observed within 4 and 7 weeks, respectively, and maintained over 20 months (patient 1, median EASI 4.2, median VAS 2; patient 2, median EASI 8.4, median VAS 2) except for one episode of exacerbation in each case. In one patient, remission was stable even after cessation of drug dosing. Severe adverse events were not observed. CONCLUSIONS: Leflunomide was efficient in the long-term treatment of recalcitrant AD. Controlled studies will be necessary to evaluate the subset of severe AD patients benefiting most from this drug.
Transplantation. 2004 May 15;77(9 Suppl):S88-92.
New drugs to improve transplant outcomes.
First MR, Fitzsimmons WE.
Fujisawa Healthcare, Inc., Deerfield, IL 60015, USA.
Fujisawa is committed to improving the outcomes of transplant patients worldwide. Research and development programs are underway for a new modified release dosage form of tacrolimus (MR-4), a new analog of leflunomide (FK 778), and several novel compounds (PG 490-88, AGI 1096) in collaboration with other companies. These programs are targeted to address many of the unmet medical needs in transplantation including (1) improving compliance, (2) reducing chronic rejection, and (3) improving long-term safety by reducing infectious and cardiovascular risk.
Clin Ther. 2004 Apr;26(4):447-59.
Leflunomide in the treatment of rheumatoid arthritis.
Li EK, Tam LS, Tomlinson B.
Department of Medicine & Therapeutics, The Chinese University
of Hong Kong, Prince of Wales Hospital, Hong Kong, ROC.
BACKGROUND: Current drug therapies for rheumatoid arthritis (RA), including nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs, help control inflammation but can cause significant toxicity. Drugs are needed that are able to suppress inflammation and modify the underlying immune response with improved tolerability. Leflunomide is an agent that affects the inflammatory process, particularly in RA. OBJECTIVE: This paper reviews the pharmacology of leflunomide, its approved use in RA, and the results of major clinical trials, including adverse events. METHODS: Relevant trials were identified through a search of the English-language literature indexed on EMBASE, MEDLINE, Current Contents, and the Cochrane Controlled Trials Register from January 1980 to November 2003. Search terms were limited to leflunomide. RESULTS: In 3 large Phase III clinical trials (US301, MN301, and MN302), leflunomide had equivalent clinical efficacy and tolerability to methotrexate and sulfasalazine and superior efficacy and tolerability compared with placebo. In US301 (N = 482), the ACR (American College of Rheumatology) 20 response rate (proportion of patients with > or =20% improvement from baseline in tender and swollen joint counts, patient's assessment of pain, patient's and physician's global assessment of disease activity, physical function, and acute-phase reactant value) at 1 year was similar with leflunomide and methotrexate and significantly greater with both active treatments than with placebo (52%, 46%, and 26%, respectively; both, P < 0.001). The efficacy of leflunomide was seen early (after 4 weeks of treatment) and was sustained throughout the study. There was less radiographic damage in both active-treatment groups compared with placebo (leflunomide, P < or = 0.001; methotrexate, P = 0.02). In MN301 (N = 358), the ACR20 response rate at 6 months was similar with leflunomide and sulfasalazine and significantly greater with both active treatments compared with placebo (55%, 56%, and 29%, respectively; both, P < 0.001). Radiographic progression was also similar with leflunomide and sulfasalazine, both of which were significantly superior to placebo (Larsen score, 0.42, 0.41, and 1.4; both, P < 0.001). An extension of this study revealed maintenance of efficacy at 12 and 24 months. In MN302 (intent-to-treat population, N = 999), 50.5% of patients in the leflunomide group were ACR20 responders at the end of 1 year, compared with 64.8% in the methotrexate group (P < 0.001 vs leflunomide). After 2 years, ACR20 response rates were similar with leflunomide and methotrexate (64.3% and 71.7%). The overall safety profile of leflunomide appears promising, although monitoring for elevations in liver enzymes and bone marrow suppression is recommended. The most common drug-related adverse events associated with leflunomide in these clinical trials were diarrhea, abnormalities in liver enzymes, rash, and hypertension.
Rheum Dis Clin North Am. 2004 May;30(2):295-309, vi.
Leflunomide.
Cannon GW, Kremer JM.
Division of Rheumatology, Department of Medicine, University of Utah,
30 North 1900 East, Salt Lake City, UT 84132, USA. grant.cannon@med.va.gov
Leflunomide is a low-molecular weight, synthetic, oral agent specifically developed for immunosuppression. Because of activity in animal models, leflunomide was tested in rheumatoid arthritis(RA). These investigations have demonstrated that leflunomide reduces the clinical symptoms and signs of RA, improves health related quality of life, and retards structural damage. Leflunomide has been evaluated in RA patients as monotherapy and in combination with methotrexate. Close monitoring for adverse events with particular attention for monitoring liver enzymes for hepatic toxicity is important during treatment with leflunomide.
Br J Clin Pharmacol. 2004 Jun;57(6):790-7.
Leflunomide in active rheumatoid arthritis: a prospective study
in daily practice.
Van Roon EN, Jansen TL, Mourad L, Houtman PM, Bruyn GA, Griep EN, Wilffert
B, Tobi H, Brouwers JR.
Department of Hospital Pharmacy and Clinical Pharmacology, Medical
Centre Leeuwarden, Leeuwarden, The Netherlands. e.n.van.roon@znb.nl
AIMS: We prospectively studied the efficacy, incidence of adverse drug reactions and withdrawal from leflunomide in an outpatient population with rheumatoid arthritis in a setting of care-as-usual. METHODS: In this prospective case series study, from outpatient medical records a standard dataset was collected including patient and disease characteristics, data on leflunomide use and adverse drug reactions. RESULTS: During the study period 136 rheumatoid arthritis patients started leflunomide. Median (range) follow-up duration was 317 (11-911) days. Sixty-five percent of patients experienced at least one adverse drug reaction related to leflunomide. During follow-up 76 patients (56%) withdrew from leflunomide treatment, mainly because of adverse drug reactions (29%) or lack of efficacy (13%). The overall incidence density for withdrawal from leflunomide was 56.2 per 100 patient-years. Complete data for calculating efficacy using a validated disease activity score on 28 joints (DAS(28)) was available for 48, 36, and 35% of patients at 2, 6, and 12 months follow-up, respectively. Within a 12-month period after start of leflunomide treatment 76% of the evaluable patients were classified as moderate or good responders according to the DAS(28) response criteria. CONCLUSIONS: In the setting of care-as-usual, rheumatoid arthritis patients starting leflunomide frequently experienced adverse drug reactions. More than half of the patients withdrew from leflunomide treatment within a year after start of leflunomide treatment, mainly because of adverse drug reactions.
J Rheumatol Suppl. 2004 Jun;71:25-30.
Lefunomide in combination therapy.
Kalden JR, Smolen JS, Emery P, van Riel PL, Dougados M, Strand CV, Breedveld
FC.
Department of Internal Medicine III, Universitaet Erlangen-Nuremberg,
Erlangen, Germany. joachim.kalden@med3.med.uni-erlangen.de
In most studies of disease modifying antirheumatic drug therapy, in combination with either leflunomide or biological agents, patients are given an additional agent after they have failed treatment with methotrexate (MTX). This review of clinical studies shows that leflunomide is clinically efficacious and well tolerated when added to either sulfasalazine or MTX, as both an initial and ongoing treatment for rheumatoid arthritis (RA). Experience in combining leflunomide with biological agents is limited to a small number of open-label studies with infliximab. According to the opinion obtained at an International Expert Panel Meeting held in Paris in May 2003, leflunomide can be used in combination therapy: 61% of the Expert Panel would use leflunomide with MTX, 71% with sulfasalazine, 43% with infliximab, 33% with adalimumab, 19% with etanercept, and 38% with anakinra. The Expert Panel stated that the combination of leflunomide and infliximab warrants a prospective, randomized, controlled trial in patients with incomplete clinical responses to leflunomide monotherapy, provided leflunomide is started first, without a loading dose, and infliximab is added after good tolerability to leflunomide has been established. The Expert Panel concluded that combination therapy with leflunomide has a place in the treatment of RA. Caution is advised, however, when using combination treatments and, therefore, the patient's safety should be carefully monitored.
J Rheumatol Suppl. 2004 Jun;71:21-4.
Leflunomide: a manageable safety profile.
van Riel PL, Smolen JS, Emery P, Kalden JR, Dougados M, Strand CV, Breedveld
FC.
Department of Rheumatology, University Medical Centre Nijmegen, Nijmegen,
The Netherlands.
The safety profile of leflunomide in the treatment of rheumatoid arthritis has been well documented in clinical trials, postmarketing surveillance, and epidemiological studies. Both postmarketing surveillance and epidemiological study results are consistent with the safety profile of leflunomide reported in clinical trials, and no increased risk was observed with leflunomide, compared with other disease modifying antirheumatic drugs; these studies have allowed a more precise representation of the incidence of adverse events occurring with leflunomide under normal conditions of care. The most common leflunomide-associated adverse events include diarrhea, elevated liver enzymes, alopecia, and rash. Ninety-five percent of the Expert Panel considered the adverse events associated with leflunomide to be manageable. If an adverse event required treatment to be stopped, many of the experts would consider subsequently restarting leflunomide. For minor adverse events, it was suggested that the physician might also consider using cholestyramine or charcoal to determine if the side effect is dose-related and, if it was, reduce the leflunomide dose accordingly. In addition to informing patients about the likelihood of side effects, it is important to emphasize that their incidence appears to diminish with continued treatment. It is also important to adequately support patients who are experiencing side effects and involve them in their disease management, for example, by offering the choice of reducing the leflunomide dose and/or having symptomatic treatment. Other patient management recommendations in this review reflect the views of the majority of participants as expressed in the meeting.
J Rheumatol Suppl. 2004 Jun;71:13-20.
The efficacy of leflunomide monotherapy in rheumatoid arthritis:
towards the goals of disease modifying antirheumatic drug therapy.
Smolen JS, Emery P, Kalden JR, Van Riel PL, Dougados M, Strand CV, Breedveld
FC.
Division of Internal Medicine III, Division of Rheumatology, Medical
University of Vienna, Vienna, Austria. smj@2me.khl.magwien.gv.at
This expert review of results from the leflunomide phase II and III clinical trials database demonstrates that leflunomide meets all 3 goals desired of disease modifying antirheumatic drug (DMARD) therapy: reducing the signs and symptoms of the disease; inhibiting structural damage; and improving physical function. Further, leflunomide has a rapid onset of action, sustained efficacy, and is effective in early and late disease, regardless of whether patients have received other DMARD previously. The consistent efficacy of leflunomide across phase III clinical trials is confirmed by the findings from clinical practice. Experts agreed that it is important to observe a patient under leflunomide monotherapy for at least 3-4 months before assessing efficacy. It is possible to start maintenance therapy, with either a daily dose of leflunomide 10 mg, subsequently changing to 20 mg, or the reverse. The decision to use a loading dose when initiating leflunomide therapy depends primarily on the balance between the tolerability and rapid efficacy associated with a loading dose, and the balance desired for an individual patient. In general, the use of both maintenance and loading doses requires a flexible approach to the treatment of rheumatoid arthritis. During the first few weeks of leflunomide therapy, patient dropout can be avoided by using prednisolone rather than a loading dose. Moreover, to ensure good tolerability and compliance in patients receiving a loading dose, information and adequate support should be provided throughout treatment.
Transplantation. 2004 May 15;77(9):1460-1.
Leflunomide therapy for cytomegalovirus disease in renal allograft
recepients.
John GT, Manivannan J, Chandy S, Peter S, Jacob CK.
Department of Nephrology, Christian Medical College, Vellore, Tamil
Nadu, India. george@cmcvellore.ac.ikn
Leflunomide has excellent antiviral activity against cytomegalovirus (CMV) in animal models and is considerably less expensive than intravenous ganciclovir. We used leflunomide in four consenting renal allograft recipients with symptomatic CMV disease, who were unable to afford ganciclovir and would otherwise remain untreated. This is the first report of efficacy of leflunomide in humans with CMV disease. They received loading dose of 100 mg of leflunomide once daily on days 1-3 and then 20 mg once daily for 3 months. All four patients were followed up three times weekly with physical examination, total leukocyte counts, blood urea and serum creatinine for a minimum period of 6 weeks. None of the patients showed drug related adverse events, alteration in cyclosporine levels, or decreased graft function, except one who developed leucopenia. Preliminary data presented suggests that leflunomide therapy for CMV disease is effective and could be used with careful monitoring in allograft recipients who cannot afford intravenous ganciclovir therapy. The duration of treatment and the role of leflunomide in secondary prophylaxis and in situations of ganciclovir resistance need to be studied further.
Br J Dermatol. 2004 May;150(5):970-6.
Leflunomide in the treatment of psoriasis: results of a phase
II open trial.
Tlacuilo-Parra JA, Guevara-Gutierrez E, Rodriguez-Castellanos MA, Ornelas-Aguirre
JM, Barba-Gomez JF, Salazar-Paramo M.
Medical Research Unit in Clinical Epidemiology, Hospital de Especialidades,
Centro Medico Nacional de Occidente, Instituto Mexicano del Seguro Social,
Guadalajara, Jalisco and Universidad de Colima, Mexico. albtlacuilo@yahoo.com
BACKGROUND: Psoriasis is recognized as the most prevalent T-cell-mediated inflammatory disease in humans, with predominantly activated T-helper (Th) 1 cell effectors. Leflunomide exerts its anti-inflammatory activities by preventing the generation of proinflammatory Th1 effectors and promoting Th2 cell differentiation. OBJECTIVES: To determine the safety and efficacy of leflunomide in patients with moderate to severe plaque-type psoriasis. METHODS: In an open-label phase II trial, eight patients with psoriasis received oral leflunomide 20 mg daily for 12 weeks. Patients were evaluated for improvement in psoriasis, quality of life, histological changes and toxicity. RESULTS: Antipsoriatic effects were obtained in all but two patients. A significant decrease was observed in the mean +/- SD Psoriasis Area and Severity Index score, from 20.08 +/- 6.85 before treatment to 12.51 +/- 11.83 after (P = 0.03). The antipsoriatic efficiency was confirmed histologically, with a significant mean +/- SD decrease in epidermal thickness, from 0.73 +/- 0.19 micro m before to 0.31 +/- 0.16 microm after (P = 0.01). The quality of life score showed an improvement, from 8.58 +/- 2.38 (mean +/- SD) before to 5.33 +/- 1.95 after (P = 0.02). The treatment was well tolerated; adverse reactions primarily consisted of transitory gastrointestinal events. CONCLUSIONS: Our data suggest that leflunomide for plaque-type psoriasis is a safe and clinically effective option as monotherapy. However, double-blind, placebo-controlled studies are needed.
Clin Exp Rheumatol. 2004 May-Jun;22(3):328-30.
Safety of leflunomide plus infliximab combination therapy in rheumatoid
arthritis.
Godinho F, Godfrin B, El Mahou S, Navaux F, Zabraniecki L, Cantagrel A.
Department of Rheumatology, Rangueil Hospital, Toulouse, France.
OBJECTIVE: To analyse the safety of leflunomide plus infliximab combination therapy, in adult rheumatoid arthritis (RA) patients. PATIENTS: A retrospective study of 17 adult patients with active RA (DAS 28 = 5.94 +/- 0.88 at baseline) who were treated with a combination of leflunomide plus infliximab after failure of treatment with other DMARDs. 13 patients were treated for a minimum of 3 months with leflunomide without toxicity before beginning infliximab. Treatment was begun simultaneously with both drugs in 4 patients. Side effects (clinical and biological) and efficacy (DAS 28) were evaluated at each infliximab infusion (3 mg/kg at week 0, 2, 6 and then every 8 weeks). RESULTS: Thirteen patients experienced 20 types of side effects and 8 of them stopped the combination therapy. The causes of discontinuation were congestive heart failure (1 case), hypertension with thoracic pain (2 cases), eczematous skin patches (2 cases) and neutropenia (3 cases). No death was registered. Nine RA patients continuted the therapy with a median follow-up of 22 weeks. Only 4 of them experienced no side effects. Eight patients were positive for antinuclear antibodies (ANA) and 1 for double-stranded DNA (dsDNA) antibodies at study entry. After treatment, 13 and 5 patients tested positive respectively for ANAs and dsDNA antibodies. There was no relationship between discontinuation and ANA/dsDNA positivity. CONCLUSION: In this cohort, adverse events were not very different from those seen in patients on either treatment alone and the combination of leflunomide plus infliximab did not appear to be as badly tolerated as described in a previous study.
Sarcoidosis Vasc Diffuse Lung Dis. 2004 Mar;21(1):43-8.
Leflunomide for chronic sarcoidosis.
Baughman RP, Lower EE.
Interstitial Lung Disease and Sarcoidosis Clinic, University of Cincinnati
Medical Center, Cincinnati, Ohio, USA. bob.baughman@uc.edu
BACKGROUND AND AIM: Leflunomide (Arava) is a cytotoxic drug which has been used as a single agent or in combination with methotrexate for the treatment of rheumatoid arthritis. It appears to have less toxicity than methotrexate. The use of leflunomide for sarcoidosis patients has not been systematically evaluated. METHODS: The records were reviewed from all patients treated at a tertiary sarcoidosis center from July 2002-July 2003, and information from patients treated with either leflunomide or methotrexate was analyzed for efficacy and toxicity. RESULTS: Thirty-two patients were treated with leflunomide; fifteen patients received concurrent therapy with methotrexate. The most common indications for therapy were ocular and lung disease. Complete or partial response to leflunomide was seen in 12 of 17 treated with leflunomide alone, and 13 of 15 treated with leflunomide plus methotrexate. There was no difference in the response rate for eye [23/28 (82%)] versus pulmonary disease [12/16 (75%)]. Seventeen patients were treated with leflunomide alone because of methotrexate toxicity (nausea in 12 and pulmonary symptoms in five). All but two tolerated leflunomide. Three patients experienced nausea leading to drug discontinuation, but no other serious adverse reaction was encountered with leflunomide. CONCLUSION: Leflunomide was well tolerated in patients with chronic sarcoidosis. It appears to be as effective as methotrexate, with less toxicity. It should be considered as an alternative in chronic sarcoidosis patients who cannot tolerate methotrexate.
