OBJECTIVE: The objective of this review is to evaluate the evidence for efficacy of methotrexate (MTX) in systemic lupus erythematosus (SLE).
METHODS: A comprehensive, computerized search was performed in MEDLINE (PubMed), EMBASE and the Cochrane Controlled Trials registry to screen for studies that examined the efficacy of MTX in adult SLE patients. The Jadad scoring system was used to assess study quality, and data were pooled using the random effects model.
RESULTS: Of the 53 articles that were identified, 44 were excluded. Nine studies (including three randomized controlled and six observational) were eligible for inclusion. All of the included studies predominantly involved patients with arthritis or mucocutaneous features. There was significant reduction of the SLE Disease Activity Index (SLEDAI) among MTX-treated patients when compared with controls (p = 0.001, odds ratio (OR) 0.444, 95% confidence interval (CI) 0.279 to 0.707). There was also significant reduction in the average dose of corticosteroids among MTX-treated patients when compared with controls (p = 0.001, OR 0.335, 95% CI 0.202 to 0.558). The effect of MTX on laboratory and serological markers, including erythrocyte sedimentation rate, anti-dsDNA and complement levels (C3 and C4), could not be determined because of the limited numbers of controlled trials.
CONCLUSION: The use of MTX is associated with significant reductions in SLEDAI and the average dose of corticosteroids in adult patients with SLE.
KEYWORDS: SLE; Systemic lupus erythematosus; efficacy; lupus; methotrexate
AIMS: The aim was to examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in patients with lupus nephritis.
METHODS: Six blood samples were drawn pre- and at 1, 2, 4, 6 and 8 h post-dose and total and unbound MPA and prednisolone pre-dose (C0 ), maximum concentration (Cmax ) and area under the concentration-time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drug-related adverse events.
RESULTS: Dose-normalized AUC varied 10-, 8-, 7- and 19-fold for total MPA, unbound MPA, total prednisolone and unbound prednisolone, respectively. Median values (95% CI) of total MPA AUC(0,8 h) (21.5 [15.0, 42.0] vs. 11.2 [4.8, 30.0] mg l(-1) h, P= 0.048) and Cmax (11.9 [6.7, 26.3] vs. 6.1 [1.6, 9.2] mg l(-1) , P = 0.016) were significantly higher in responders than non-responders. Anaemia was significantly associated with higher total (37.8 [14.1, 77.5] vs. 18.5 [11.7, 32.7] mg l(-1) h, P = 0.038) and unbound MPA AUC(0,12 h) (751 [214, 830] vs. 227 [151, 389] mg l(-1) h, P = 0.004). Unbound prednisolone AUC(0,24 h) was significantly higher in patients with Cushingoid appearance (unbound: 1372 [1242, 1774] vs. 846 [528, 1049] nmol l(-1) h, P = 0.019) than in those without. Poorer treatment response was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023).
CONCLUSIONS: This study suggests a potential role for therapeutic drug monitoring in individualizing immunosuppressant therapy in patients with lupus nephritis.
KEYWORDS: lupus nephritis; mycophenolic acid; pharmacodynamics; pharmacokinetics; prednisolone; treatment outcome
Study site: Nephrology and SLE Clinics, Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia
BACKGROUND AND OBJECTIVE: Mycophenolic acid (MPA) provides effective treatment for lupus nephritis patients. Owing to its large pharmacokinetic variability, it is questionable whether standard fixed dose therapy can achieve optimal MPA exposure. The aim of this study was to develop a population pharmacokinetic model of MPA and its metabolite, 7-O-MPA-β-glucuronide (MPAG), to identify important covariate influences and better predict patient dosing requirements.
METHODS: MPA and MPAG concentration-time profiles were collected from 25 patients receiving mycophenolate mofetil (MMF) with or without cyclosporine (CsA) co-therapy. Samples were collected pre-dose and at 1, 2, 4, 6 and 8 h post-dose on one or two occasions.
RESULTS: A total of 225 and 226 concentration-time measurements of MPA and MPAG, respectively, were used to develop the model, utilizing NONMEM® software. A two-compartment model with first-order absorption and elimination for MPA and a one-compartment model with first-order elimination and enterohepatic circulation (EHC) for MPAG best described the data. Apparent clearance of MPAG (CL/F MPAG) significantly decreased with reducing renal function and extent of EHC was reduced with concomitant CsA use. Simulations using the final model showed that a 70-kg subject with a creatinine clearance of 90 mL/min receiving concomitant CsA would require 1.25 g of MMF twice daily while a similar subject who did not receive concomitant CsA would require 0.75 g twice daily to achieve a MPA area under the concentration-time curve from 0 to 12 h (AUC0-12) of 45 mg·h/L.
CONCLUSION: A 'tiered' dosing approach considering patient renal function and CsA co-therapy, rather than a 'one dose fits all' approach, would help individualize MMF therapy in adult lupus nephritis patients to ensure more patients have optimal MPA exposure.
Study site: Nephrology and Systemic Lupus Erythematosus (SLE) Clinics, Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia
Matched MeSH terms: Immunosuppressive Agents/therapeutic use
Mycophenolate is an immunosuppressive agent which has been used in systemic lupus erythematosus (SLE) patients who have failed conventional therapy. However, the use of mycophenolate sodium in extra-renal SLE involvement has yet to be established. This study aimed to assess the efficacy of mycophenolate sodium in extra-renal SLE.
Chronic intestinal pseudo-obstruction (CIPO) is a rare clinical syndrome of ineffective intestinal motility characterised by clinical and radiological evidence of intestinal obstruction with no identifiable mechanical lesion. CIPO can either be idiopathic or secondary to a systemic disease, like systemic lupus erythematosus (SLE). Fewer than 30 cases of CIPO secondary to SLE have been reported so far. Here we describe a case of SLE with the initial presentation of CIPO. In SLE-related CIPO, treatment includes a combination of high-dose intravenous corticosteroids, immunosuppressants and supportive care. With awareness of this condition, unnecessary surgical intervention and repeated invasive procedures could be avoided. Early initiation of treatment would avoid complications and bring about resolution of symptoms.
A 33-year-old man presented with a four-day history of redness and blurring of vision of the right eye. A clinical diagnosis of adenoviral keratitis was made with a differential of microsporidia epithelial keratitis. The patient subsequently developed nummular keratitis which was resistant to topical steroids. He continued to develop multiple recurrences of the condition. Treatment with tacrolimus ointment was started as the patient had an elevated intraocular pressure due to prolonged steroid use. Tacrolimus ointment showed a favourable outcome in the management of recurrent nummular keratitis.
Cyclosporine is a primary drug in transplant immunosuppression regimens. It has a narrow therapeutic index and variable pharmacokinetic behavior. This study aimed to develop a population pharmacokinetic model of cyclosporine in Malaysian renal transplant recipients as well as to evaluate the performances of different methodsfor handling missing doses. A total of 2804 concentrationts predose and 2 hours after doses were collected retrospectively from 113 renal transplant patients on cyclosporine in Penang General Hospital. Model structure and pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling software. Missing doses were handled using different methods to evaluate their performance. Covariate analysis was performed using stepwise forward addition (P < .05) followed by backward elimination (P < .001). Prediction-corrected visual predictive check and sampling-importance resampling methods were used to validate the final model. A 1-compartment model with first-order absorption and elimination best fitted the data. All methods to handle missing doses performed well with the missing dose method being superior to other methods and thus was applied in the final model. Cyclosporine clearance (CL/F) was estimated as 15.1 L/h, and volume of distribution (V/F) was 108 L. Postoperative time, sex, and calcium channel blockers were identified as significant covariates on CL/F, whereas sex and cholesterol level were identified as significant covariates on V/F. This is the first population pharmacokinetic model developed in Malaysian renal transplant patients using a large sample with an evaluation of different methods to handle missing doses in less informative conventional therapeutic drug-monitoring data.
Matched MeSH terms: Immunosuppressive Agents/therapeutic use
Tacrolimus (FK506) is a calcineurin inhibitor with a narrow therapeutic index that exhibits large interindividual variation. Seventy-eight kidney transplant patients treated with tacrolimus were recruited to study the correlation of dose adjusted trough level (level/dose; L/D) of tacrolimus with CYP3A5 and ABCB1 genotypes, as well as the mRNA copy number of ABCB1 in blood. Patients were genotyped for ABCB1 (C1236T, G2677T/A, and C3435T) and CYP3A5 (G6986A), while ABCB1 mRNA transcript copy number was determined by absolute quantification (real-time PCR) in 46 patients. CYP3A5*3 genotypes were found to be a good predictor of tacrolimus L/D in kidney-transplant patients. Significantly higher L/D was observed among non-expressors (2.85, 95%: 2.05-3.70 (ng·mL(-1))/(mg·kg(-1))) as compared with the expressors (1.15, 95%: 0.95-1.80 (ng·mL(-1))/(mg·kg(-1))) of CYP3A5 (Mann-Whitney U test; P < 0.001). No correlation was observed between L/D and the ABCB1 genotypes. A significant inverse correlation of blood ABCB1 mRNA level with L/D was demonstrated (Spearman's Rank Order correlation; P = 0.016, rs = -0.348). However, in multiple regression analysis, only CYP3A5*3 genotype groups were found to be significantly correlated with tacrolimus L/D (P < 0.001). These findings highlight the importance of CYP3A5*3 pharmacogenotyping among kidney-transplant patients treated with tacrolimus, and confirm the role of blood cell P-glycoprotein in influencing the L/D for tacrolimus.
A 20-year-old girl first notice bilateral ocular muscle weakness in 2001. Two months later, she developed acute muscle paralysis and respiratory failure which required ventilation. Serum anti-acetylcholine receptor antibodies and repetitive nerve stimulation test was positive and consistent with myasthenia gravis (MG). CT scan thorax revealed thymic enlargement and she underwent a video assisted thymectomy (VATS). However, over the next three years, despite maximal doses of various immunosuppressive agents with plasmapheresis and intravenous immunoglobulin, she was admitted with recurrent myasthenic crisis without any obvious precipitant. She was then commenced on mycophenolate mofetil and together with regular plasmapheresis, cyclosporine and prednisolone, her symptoms have finally improved and brought under control.
Inflammatory bowel disease (IBD) has increased in incidence and prevalence in Asian countries since the end of the 20th century. Moreover, differences in the cause, phenotypes, and natural history of IBD between the East and West have been recognized. Therefore, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have established recommendations on medical management of IBD in Asia. Initially, the committee members drafted 40 recommendations, which were then assessed according to Grading of Recommendations Assessment, Development and Evaluation. Eight statements were rejected as this indicated that consensus had not been reached. The recommendations encompass pretreatment evaluation; medical management of active IBD; medical management of IBD in remission; management of IBD during the periconception period and pregnancy; surveillance strategies for colitis-associated cancer; monitoring side effects of thiopurines and methotrexate; and infections in IBD.
Matched MeSH terms: Immunosuppressive Agents/therapeutic use
Intravenous immunoglobulin (IVIG), corticosteroids and therapeutic plasma exchange (TPE) are evidence-based conventional treatments for chronic inflammatory demyelinating polyneuropathy (CIDP). In many centres, unconventional treatments are frequently used as alternatives. We evaluated the outcome of conventional and unconventional therapies in 31 CIDP patients. Overall response rate with conventional first-line immunotherapies was 77% (20/26), comparable between IVIG and corticosteroids (80% vs 70%). Use of TPE was limited. Treatment response among typical and atypical CIDP were comparable (76 vs 80%). Non-responders were patients with progressive form of typical CIDP and DADS. Majority (21/26, 81%) of patients with persistent neurological deficits received maintenance therapy. Two subgroups of patients frequently treated with maintenance immunosuppressants were those with improving or stable disease following first-line treatment (12, 57%) and those with progressive form of CIDP (2, 10%). Primary indications for immunosuppressant use were corticosteroids-sparing and additional immunosuppression effects. Nine (64%) patients with improving or stable disease given azathioprine were taken off corticosteroids after a median duration of 14 months (range 12-108). Two (14%) eventually achieved cure or clinical remission without treatment. Maintenance IVIg was given to 6 (29%) relapsing CIDP patients; none of achieved cure or remission after similar median duration of treatment. Less potent immunosuppressant drugs (azathioprine, mycophenolate mofetil, and methotrexate) were frequently used, with moderate adverse effect profiles. In resource limited setting, unconventional treatments were commonly used among CIDP patients with different clinical course of progression. In most cases, careful risk-benefit re-assessment is required to justify its further use.
Long-term outcome in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is very limited, especially from Asian countries. We aimed to determine the outcome of our cohort of CIDP patients and to define the relevant clinical, electrophysiological and laboratory determinants of disease activity, progression and treatment response. We retrospectively reviewed records of 23 CIDP patients attending our Neurology service at Kuala Lumpur Hospital, Malaysia between January 2000 and December 2016. We analysed data on neurological deficits, electrophysiological and laboratory parameters to determine diagnostic characteristics, correlation with disease activity and clinical outcomes following treatment. Included were 15 (65%) males and 8 (35%) females with a mean age of 42.7 years (SD 14.4). Mean duration of follow-up visit was 66 months (range 6-134 months). The cohort consists of 19 classical (sensory-motor) CIDP and 4 MADSAM. Large majority of patients (66%) had either stable active disease (CDAS 3, 44%) or were in remission (CDAS class 2, 22%) following treatment with standard immunotherapies (Intravenous Immunoglobulins, steroids or immunosuppressants). The proportion of CIDP patients in each CDAS class was comparable to published cohorts from North America and Europe. Medical Research Council (MRC) sum score was the only clinical score that differed across CDAS classes (p = .010) with significant inverse correlation (Spearman's rho -0.664, p = .001). In conclusion, treatment outcomes of our CIDP cohort was comparable to those of published series. Further studies with larger cohort of patients from other parts of Asia are important to determine the long-term outcome of this heterogenous disease in this region.
BACKGROUND: Little is known about autoimmune liver disease (AILD) in Asian children. We studied the clinical features and predictors of outcome in childhood AILD in an Asian population.
METHODS: Retrospective review of AILD [autoimmune hepatitis type 1 and 2 (AIH1, AIH2), primary sclerosing cholangitis (PSC) and autoimmune sclerosing cholangitis (ASC)] seen at two pediatric liver units in Malaysia.
RESULTS: At presentation, 17 (56%) of the 32 children [19 females, 59%; median (range) age 7.7 (1.8-15.5) years] with AILD (AIH1 = 18, AIH2 = 5, PSC = 0, ASC = 9) had liver cirrhosis. At final review [median (range) duration of follow-up 4.8 (0.4-12) years], 24 patients (75%) survived with a native liver. Twenty-one (66%) were in remission; 19 (AIH1 = 11; AIH2 = 4, ASC = 4) were on prednisolone and/or azathioprine, one on cyclosporine and another on mycophenolate mofetil. Three (AIH1 = 3) were in partial remission. Of the two who underwent liver transplantation (LT; 6.5%; both ASC), one died of primary graft failure after LT. Six patients (19%) died without LT (acute liver failure, n = 1; end-stage liver disease, n = 5). The overall survival rate (native liver and survival post-LT) was 78%. A delay in seeking treatment adversely affected the final outcome [survival with native liver vs. LT or death (duration between onset of disease and treatment; median ± standard error) = 2.5 ± 2.9 months vs. 24.0 ± 13.3 months; p = 0.012].
CONCLUSIONS: Although remission was achieved in the majority of patients with prednisolone and/or azathioprine therapy, delay in seeking diagnosis and treatment adversely affects the outcome of childhood AILD in Malaysia.
Matched MeSH terms: Immunosuppressive Agents/therapeutic use
Hypercementosis is excessive deposition of non-neoplastic cementum over normal root cementum, which alters root morphology. This cementum may be either hypocellular or cellular in nature. The aetiopathogenesis of hypercementosis is ambiguous. Although most of the cases are idiopathic, several local and systemic factors are also linked to this condition, such as Paget's disease, acromegaly, vitamin A deficiency, etc. We report two rare cases of hypercementosis associated with systemic lupus erythematosus, not previously described in the literature, and also discuss the possible aetiopathogenesis.
Matched MeSH terms: Immunosuppressive Agents/therapeutic use
Patients with autoimmune connective tissue disease may manifest as overlap syndrome with features of systemic lupus erythematosus (SLE), systemic sclerosis, rheumatoid arthritis and myositis. Those presenting with active SLE can present with immune thrombocytopenia (IT) and may be complicated with subdural hematoma which, though rare, is potentially life-threatening. We report here a patient with overlap syndrome who had recurrent spontaneous subdural hematoma due to severe thrombocytopenia which did not respond to corticosteroids and azathioprine. Her platelet count became normal with three doses of low-dose intravenous cyclophosphamide (IV CYC) given at 3-weekly intervals. She remained in remission with maintenance therapy with azathioprine.
Matched MeSH terms: Immunosuppressive Agents/therapeutic use
Necrotising pneumonia or lung gangrene is a challenging problem and it is diagnosed more often today, especially in tertiary hospitals. It is always a challenge to treat these patients as they are usually immunocompromised and are often ill when the diagnosis is made. We report three immunocompromised patients with necrotising pneumonia who were treated surgically. We share the outcomes of these patients and discuss the management of necrotising pneumonia in the immunocompromised.
Matched MeSH terms: Immunosuppressive Agents/therapeutic use