Sequential study on the treatment of moderate-to-severe chronic plaque psoriasis with mycophenolate mofetil and cyclosporin

BACKGROUND: There are numerous studies that individually evaluate the efficacy/effectiveness and toxicity of drugs in the systemic treatment of psoriasis. On the contrary, we can hardly find studies that compare each other. OBJECTIVE: To evaluate and compare the effectiveness and toxicity of mycophenolate mofetil and cyclosporin in chronic plaque psoriasis through a prospective, sequential, cross-over, non-randomized, two-phase, open-label study. PATIENTS/METHODS: Eight patients (five women and three men; mean age 57, range 35-78) with moderate-to-severe chronic plaque psoriasis were included in the study. They were treated with oral mycophenolate mofetil (30 mg/kg/day) over a period of 16 weeks. Following a variable washout period and after a new outbreak of the disease, oral cyclosporin was introduced at a dose of 4 mg/kg/day. During both treatment regimens, follow-up visits were performed at 3, 8 and 16 weeks. RESULTS: In both groups, the PASI started to decrease once treatment was begun. Cyclosporin was faster and statistically a lot more effective than mycophenolate mofetil, reaching a higher number of complete remissions and better percentages of PASI improvement from baseline (45.7%, 60.2% and 60.5% at 3, 8 and 16 weeks respectively for mycophenolate mofetil, and 89.7%, 95.3% and 95.3% respectively at the same intervals for cyclosporin). Cyclosporin was also more predictable in its action as the percentage of improvement along the follow-up visits had a much wider range for mycophenolate mofetil. Overall, the tolerability of both drugs was good. None of the patients had to discontinue treatment because of an adverse event. Two patients treated with cyclosporin showed increased plasma levels of creatinine. CONCLUSIONS: Cyclosporin is more effective, fast, and predictable in its effect than mycophenolate mofetil to control moderate-to-severe chronic plaque psoriasis. Both drugs are well tolerated in short courses of treatment.     

Change of treatment from cyclosporin to mycophenolate mofetil in severe psoriasis

Eight patients whose severe psoriasis was treated with long-term cyclosporin (range 2-11 years; mean 7.6 years) were changed to mycophenolate mofetil (MMF), because of nephrotoxicity in seven and hypertension and lack of efficacy in one. In five patients psoriasis control significantly deteriorated and in three patients disease control deteriorated slightly in periods ranging from 2 to 32 weeks. Renal function improved in all six patients with cyclosporin-induced nephrotoxicity treated with MMF for more than 2 weeks. From this data it would appear that MMF is not as effective as cyclosporin in controlling severe psoriasis. However, MMF did offer reasonable disease control in three of eight patients and allowed renal function to improve, and so may have a place in the treatment of some patients unable to take cyclosporin because of renal toxicity.     

Plasma trough levels of mycophenolic acid do not correlate with efficacy and safety of mycophenolate mofetil in psoriasis

BACKGROUND: Mycophenolate mofetil (MMF) has been shown to be effective for systemic treatment of psoriasis. MMF is the prodrug of mycophenolic acid (MPA), the pharmacologically active compound. The measurement of plasma MPA levels could be useful for optimizing therapeutic management using MMF. OBJECTIVES: To investigate whether plasma trough levels of MPA correlate with the efficacy and safety of oral MMF in the treatment of patients with psoriasis. METHODS: Six patients (four women and two men, mean age 58 years) with severe chronic plaque-type psoriasis were treated with oral MMF 1 g twice daily. The Psoriasis Area and Severity Index (PASI), routine laboratory examinations and plasma MPA trough levels, measured by an enzyme-multiplied immunoassay (EMIT), were determined at 2 weeks and 1, 3, 5 and 7 months. RESULTS: All the patients experienced a marked improvement within the first 15 days and continued to do so for 5-7 months. Two patients achieved complete remission. MMF was well tolerated. MPA levels showed a wide intra- and interindividual variability. There was no significant correlation between MPA trough levels and the reduction of the PASI or the presence of adverse effects, but a good correlation with therapeutic compliance. CONCLUSIONS: The monitoring of MPA trough levels with EMIT appears to be a poor predictor of efficacy or toxicity. In contrast, it is a useful tool to evaluate the degree of therapeutic compliance.     

Use of mycophenolate mofetil in the treatment of paraneoplastic pemphigus

Paraneoplastic pemphigus (PNP) is a rare autoimmune blistering disease with circulating antibodies that bind the cell surface of the epidermis and other non-stratifying epithelia, and immunoprecipitate a complex of four or five proteins (250 kDa, 230 kDa, 210 kDa, 190 kDa and occasionally 170 kDa).1,2 Combinations of immunosuppressive agents are usually required to obtain even partial control of the skin lesions.3 Mucous membrane lesions are refractory to treatment. We describe a patient with PNP whose skin and oral lesions are quiescent following treatment with oral mycophenolate mofetil.     

Widespread plaque psoriasis responsive to mycophenolate mofetil

A woman with a long history of widespread plaque psoriasis unresponsive to and/or intolerant of phototherapy, retinoids, methotrexate and cyclosporin was successfully treated with mycophenolate mofetil. Remission was maintained on doses between 1 and 1.5 g/day for 18 months without adverse effects.     

Successful treatment of subacute cutaneous lupus erythematosus with mycophenolate mofetil

Mycophenolate mofetil (MMF) is an immunosuppressive agent that has been shown to be effective in transplant patients. Some case reports and pilot studies have suggested efficacy against systemic lupus erythematosus (LE), particularly in the case of lupus nephritis. Reports on MMF treatment of skin manifestations of LE are still anecdotal. We report two cases with extensive skin lesions owing to subacute cutaneous LE (SCLE). Both patients had been treated with azathioprine and antimalarials without effect. Finally both patients were given highly dosed glucocorticosteroids, which were also ineffective but led to vertebral fractures because of long-term steroid treatment in one patient and steroid-induced psychosis in the other. MMF 2 g daily caused the skin manifestations to disappear within a few weeks in both patients. One patient was followed up for more than 24 months, and showed good toleration of MMF treatment. The skin remained stable over this period when at least 1 g MMF per day was administered. In conclusion, MMF appears to be an attractive treatment option in skin manifestations of SCLE, and seems to be beneficial for patients with steroid-refractory lesions that are also resistant to treatment with immunosuppressants or antimalarials. The observations suggest that further evaluation of this route in randomized controlled trials is warranted.     

Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION)

BACKGROUND: Biologic therapies such as adalimumab, a tumour necrosis factor antagonist, are safe and effective in the treatment of moderate to severe chronic plaque psoriasis. OBJECTIVES: To compare a biologic agent with methotrexate, a traditional systemic agent, to define clearly the role of biologics in psoriasis. METHODS: Patients with moderate to severe plaque psoriasis were randomized to adalimumab (80 mg subcutaneously at week 0, then 40 mg every other week, n=108), methotrexate (7.5 mg orally, increased as needed and as tolerated to 25 mg weekly; n=110) or placebo (n=53) for 16 weeks. The primary efficacy endpoint was the proportion of patients achieving at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75) after 16 weeks. Safety was assessed at all visits through week 16. RESULTS: After 16 weeks, 79.6% of adalimumab-treated patients achieved PASI 75, compared with 35.5% for methotrexate (P<0.001 vs. adalimumab) and 18.9% for placebo (P<0.001 vs. adalimumab). Statistically significantly more adalimumab-treated patients (16.7%) than methotrexate-treated patients (7.3%) or placebo-treated patients (1.9%) achieved complete clearance of disease. The response to adalimumab was rapid, with a 57% improvement in mean PASI observed at week 4. Adverse events were similar across treatment groups. Adverse events leading to study discontinuation were greatest in the methotrexate group, primarily because of hepatic-related adverse events. CONCLUSIONS: After 16 weeks, adalimumab demonstrated significantly superior efficacy and more rapid improvements in psoriasis compared with either methotrexate or placebo.     

Efficacy and safety of cyclosporine versus methotrexate in severe psoriasis: a study from north India

Treatment of patients with severe psoriasis is difficult. Among the number of systemic drugs that are available, methotrexate has long been used, but cyclosporine has been recently recommended for the management of severe psoriasis. The purpose of this study was to compare the efficacy and safety of daily cyclosporine with weekly methotrexate in the management of severe psoriasis. Thirty consecutive patients with severe psoriasis were randomly assigned to treatment with cyclosporine or methotrexate. The initial dose of cyclosporine was 3 mg/kg/day, which was increased to a maximum of 4 mg/kg after two weeks of therapy when the response was not adequate. Methotrexate was administered weekly at a dose of 0.5 mg/kg. Clinical response was assessed by calculating PASI score in all patients at biweekly intervals. Patients were followed up fortnightly up to a maximum of 12 weeks. The doses of both drugs were gradually tapered once >75% reduction in disease severity was attained. Marked improvement (>75%) reduction in PASI was noted in all patients except for one in the cyclosporine group. The median time for marked improvement was 5.3 weeks with methotrexate and 6.8 weeks with cyclosporine. Patients on methotrexate were found to have more rapid and complete clearance than those on cyclosporine. Both drugs were well tolerated. Side effects in both the treatment groups were minor, transient, and manageable. At doses with comparable safety profiles, methotrexate resulted in more rapid and cost effective clearance of patients with severe psoriasis. Cyclosporine can provide an effective and safe alternative.     

Pneumonitis complicating methotrexate therapy for pustular psoriasis.

We report a patient with pustular psoriasis who developed interstitial pneumonitis after receiving weekly methotrexate (MTX) therapy at an average dose of 20 mg for 26 years. The patient responded dramatically to withdrawal of the drug and administration of corticosteroids. Pulmonary toxicity is a rare adverse effect of MTX therapy and is particularly uncommon in psoriatics. As interstitial pneumonitis is a potentially fatal but reversible complication, early respiratory symptoms even in patients on low-dose MTX treatment should be appropriately investigated.     

Treatment of atopic eczema with oral mycophenolate mofetil

BACKGROUND: Activated T and B lymphocytes are the predominant inflammatory cells in atopic eczema (AE) lesions. Mycophenolic acid, the active form of mycophenolate mofetil (MMF), blocks the proliferative responses of T and B lymphocytes. OBJECTIVES: In this pilot study, we examined the efficacy of MMF (CellCept(R), Hoffman La Roche, Grenzach-Wyhlen, Germany) in severe AE. METHODS: Ten patients with severe AE (severity index > 50) according to the Severity Scoring of Atopic Dermatitis (SCORAD) index were treated with oral MMF at an initial dose of 1 g daily during the first week and 2 g daily for a further 11 weeks. Laboratory examination including full blood count, lymphocyte subset analysis, serum immunoglobulins (IgE, IgG, IgM, IgA), total bilirubin, alkaline phosphatase, aminotransferases, lactate dehydrogenase and creatinine was performed every 2 weeks. Additionally, interleukin (IL)-10 and interferon (IFN)-gamma in serum were measured. RESULTS: None of the 10 patients who received MMF discontinued the trial because of lack of efficacy or adverse events. Compared with the baseline, the median scores for disease severity (SCORAD index) improved by 68% during treatment with MMF. The median serum IgE level decreased significantly, from 10,300 kU L-1 before treatment to 7830 kU L-1 after 12 weeks. MMF induced a significant increase in the T-helper (Th)-1-related cytokine IFN-gamma and a significant decrease in IL-10, mainly produced by Th2 cells. CONCLUSIONS: The present study demonstrates that oral MMF at a dose of 2 g daily is an effective, safe and well-tolerated immunosuppressive therapy for severe AE in adults.     

小剂量阿维A与MTX联合治疗重症寻常型银屑病随机对照研究

目的:观察小剂量阿维A与甲氨蝶呤(MTX)联合治疗重症寻常型银屑病的疗效与不良反应。方法:观察组:阿维A0.3mg(kg·d),MTX2.5mg,12h1次,每周连服3次,辅以叶酸5mgd,维生素E300mgd,用药6周。对于6周内临床治愈的病人,先停用MTX,阿维A减半维持治疗2周,停药。对照组1:阿维A0.3mg(kg·d),3～5d后加至0.5mg(kg·d),叶酸和维生素E同观察组,用药6周;对照组2:MTX5mg,12h1次,每周连服3次,叶酸和维生素E同观察组,用药6周。结果:观察组、对照组1和对照组2的有效率分别为96.23%、65.54%和66.67%。三组相比有显著性差异(χ2=9.97,P<0.01)。三组间不良反应发生率分别为11.32%、33.33%和27.27%,有显著性差异(χ2=8.67,P<0.05)。结论:小剂量阿维A与小剂量MTX联合治疗重症寻常型银屑病疗效好,不良反应发生率低。     

Combination treatment with methotrexate and cyclosporin for severe recalcitrant psoriasis

An increasingly important approach to the management of patients with severe psoriasis is the concurrent use of two systemic treatments. Previous guidelines have advised against the use of methotrexate and cyclosporin in combination. We report the successful use of a combination of methotrexate and cyclosporin in the treatment of 19 patients with severe, recalcitrant psoriasis, 15 of whom had psoriatic arthropathy. Most patients had previously received two or more systemic treatments. Before combination treatment was started nine of the patients were taking methotrexate and 10 were taking cyclosporin at the maximum tolerated doses. The duration of combination treatment was bimodally distributed, with seven patients having short-term treatment (mean +/- SD duration 18. 9 +/- 15.7 weeks) and 12 patients having long-term treatment (mean +/- SD duration 193.2 +/- 160.6 weeks). Those patients who received short-term treatment did not develop any evidence of toxicity from either agent. Of those patients on long-term treatment, three developed mild impairment of renal function that returned to normal following a reduction in dose of cyclosporin, and three had impairment of renal function (following long-term cyclosporin monotherapy) that improved, but did not normalize, following a reduction in dose of cyclosporin. In each case, combination treatment for psoriasis resulted in good control of both skin and joint problems using lower doses of each agent than would have been used for monotherapy. We conclude that the combination of methotrexate and cyclosporin is an effective treatment for this group of patients.     

Subcutaneous methotrexate versus oral form for the treatment and prophylaxis of chronic plaque psoriasis

Psoriasis is a common inflammatory skin disorder with complex pathomechanisms. Methotrexate (MTX) is an antiproliferative and immunomodulating agent that control psoriasis. The aim of this study is to compare the efficacy of MTX and tolerability to MTX by oral route versus subcutaneous (SC) route. Twenty‐eight cases were divided into two equal groups: Group I received a weekly dose of oral MTX and Group II received a weekly dose of SC MTX for 12 weeks. The starting dose was 7.5–10 mg and increased gradually by 2.5 mg every month till reaching 12.5–15 mg/week. Patients' clinical responses were evaluated according to Psoriasis Area and Severity Index (PASI) score. Results suggest that Group I patients showed reduction in PASI score of mean ± SD from 19 ± 7.4 before treatment to 11.2 ± 6.29 after treatment while Group II patients showed reduction from 23.4 ± 14.7 before treatment to 2.55 ± 2.6 after treatment with highly statistically significant difference between both groups. Clinical improvement was complete in 7.1% of Group I versus 57.1% of Group II. In conclusion, SC MTX has higher efficacy with lesser adverse effects and lower relapse rate when compared to oral form given by the same dose during the same duration.     

Long-term maintenance treatment of moderate-to-severe plaque psoriasis with infliximab in combination with methotrexate or azathioprine in a retrospective cohort

Background  Effective, fast-acting and safe therapies are needed for long-term maintenance treatment of psoriasis. In October 2005, infliximab was approved for the treatment of moderate-to-severe plaque psoriasis, but long-term data are limited.
Objective  To evaluate the effectiveness of infliximab, used in combination with methotrexate or azathioprine, in maintaining clinical benefit in patients with moderate-to-severe psoriasis.
Methods  The medical charts of 23 patients treated with infliximab from August 2001 to February 2007 were retrospectively reviewed. Most patients received either infliximab 3 mg/kg (17 of 23) or 5 mg/kg (1 of 23) in combination with methotrexate, while 5 of 23 patients received infliximab 5 mg/kg in combination with azathioprine. Psoriasis Area Severity Index (PASI) score and adverse events were recorded at every infliximab infusion visit at the hospital.
Results  Patient data were available for a minimum of 4 weeks and up to 5 years and 5 months. At week 14, 91.3% achieved PASI 50, 69.6% achieved PASI 75, and 39.1% achieved PASI 90. Only two patients discontinued therapy due to loss of response: one after 15 months and one after 3 years. All other patients displayed a good clinical response (≥ PASI 50) and were still receiving this regimen at last observation. Combination regimens of infliximab with methotrexate or azathioprine were well tolerated, and only one patient discontinued therapy because of an adverse event (lung embolism) after two infusions with infliximab.
Conclusions  Long-term (> 1 year) maintenance therapy of infliximab combined with methotrexate or azathioprine is effective and well tolerated for moderate-to-severe plaque-type psoriasis.

Conflicts of interest

None declared     

甲氨蝶呤治疗银屑病应用专家共识

甲氨蝶呤(MTX)是一种免疫抑制剂,最初用于恶性肿瘤的治疗,目前在许多自身免疫性疾病和炎症性皮肤病的治疗中也占有重要地位。近年来,来自高质量随机双盲试验(RCT)的大量数据进一步证实MTX在银屑病治疗中的疗效以及安全性。MTX的毒副作用也逐步明确,在密切监测下,可以安全地应用于银屑病及其他皮肤疾病的治疗。尽管目前有大量的生物制剂及小分子靶向药物上市,但MTX作为治疗银屑病的传统药物,对于国内广大银屑病患者治疗依然有不可替代的作用。该共识的总体目标是对MTX在银屑病治疗中的应用研究现状、用药前评估、常规给药方法、不良反应、毒副作用评估和处理等方面进行介绍与规范,为MTX在中国银屑病患者中有效及安全地应用提供建议。     

霉酚酸酯与环磷酰胺治疗狼疮性肾炎的疗效对比

为了观察霉酚酸酯治疗狼疮性肾炎的疗效及安全性,设置霉酚酸酯+泼尼松为治疗组和环磷酰胺+泼尼松为对照组,对肾活检确诊为狼疮性肾炎的患者进行临床疗效对比观察。结果发现治疗组虽有半数患者对环磷酰胺耐药,但疗效仍与对照组相当(P>0.05),而泼尼松减量速度则比对照组快(P<0.01)。提示霉酚酸酯治疗狼疮性肾炎的疗效优于环磷酰胺。     

Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms

Background  The use of methotrexate is limited by interindividual variability in response. Previous studies in patients with either rheumatoid arthritis or psoriasis suggest that genetic variation across the methotrexate metabolic pathway might enable prediction of both efficacy and toxicity of the drug.
Objectives  To assess if single nucleotide polymorphisms (SNPs) across four genes that are relevant to methotrexate metabolism [folypolyglutamate synthase ( FPGS ), gamma-glutamyl hydrolase ( GGH ), methylenetetrahydrofolate reductase ( MTHFR ) and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase ( ATIC )] are related to treatment outcomes in patients with psoriasis.
Methods  DNA was collected from 374 patients with psoriasis who had been treated with methotrexate. Data were available on individual outcomes to therapy, namely efficacy and toxicity. Haplotype-tagging SNPs ( r ² > 0·8) for the four genes with a minor allele frequency of > 5% were selected from the HAPMAP phase II data. Genotyping was undertaken using the MassARRAY spectrometric method (Sequenom^®).
Results  There were no significant associations detected between clinical outcomes in patients with psoriasis treated with methotrexate and SNPs in the four genes investigated.
Conclusions  Genetic variation in four key genes relevant to the intracellular metabolism of methotrexate does not appear to predict response to methotrexate therapy in patients with psoriasis.     

Efficacy of oral methotrexate (MTX) monotherapy vs oral MTX plus narrowband ultraviolet light B phototherapy in palmoplantar psoriasis

Palmoplantar psoriasis (PPP) is a chronic, inflammatory dermatosis of the palms and/or soles with significant morbidity. It is notoriously difficult to treat and unresponsive to traditional topical agents. We aim to compare the effect of oral methotrexate (MTX) monotherapy vs MTX plus narrowband ultraviolet light B (NB‐UVB) in the treatment of recalcitrant PPP. This was a comparative clinical trial involving 90 patients of PPP. Eligible patients were randomly assigned to one of the two treatment groups. We aim patients in group A received 10 mg oral MTX weekly, and patients in group B received oral MTX 10 mg weekly and NB‐UVB sessions twice weekly for 12 weeks. There was a statistically significant difference in reduction of modified PPP Area Severity Index (m‐PPPASI) of patients in MTX plus NB‐UVB at week 12. The mean m‐PPPASI at week 12 was 3.66 ± 2.11 in MTX plus NB‐UVB group and 6.51 ± 2.04 in MTX only group (P < .001). Marked improvement (m‐PPPASI 75) was achieved in 20 (44.44%) patients in MTX plus NB‐UVB group compared with 6 (13.3%) in MTX monotherapy group (P < .001). Combination of MTX and NB‐UVB phototherapy helps to attain a better clinical response (reduction in m‐PPPASI score) than MTX monotherapy in the treatment of recalcitrant PPP.     

Pulmonary function changes in patients with psoriasis on methotrexate therapy.

Methotrexate is known to induce pulmonary fibrosis. The present study was undertaken to assess pulmonary toxicity, if any, in psoriasis patients on methotrexate therapy and correlate the dose and duration of the treatment with any changes in pulmonary function. Ten patients who had taken methotrexate for one year and ten patients receiving methotrexate were included in the present study. Detailed lung function studies including arterial blood gas analysis were carried out. In both groups, the only pulmonary function abnormalities detected were FEF200-1200, FEF25-75%, residual volume (RV), and RV/TLC%, which showed a decline after six months of treatment. However, this was not significant. No changes were detected in the arterial blood gas values following methotrexate therapy. Therefore, the present study did not find any significant deterioration of lung functions in psoriasis patients on methotrexate therapy.