Rhabdomyolysis and acute kidney injury potentiated by a drug-drug interaction between cyclosporine, leflunomide, and rosuvastatin in a kidney transplant recipient: A missed opportunity for pharmacist involvement.

BACKGROUND: This study aimed to describe a case of rhabdomyolysis and acute kidney injury potentiated by a drug-drug interaction (DDI) between cyclosporine, leflunomide, and rosuvastatin in a kidney transplant recipient. CASE SUMMARY: A 74-year-old male with end-stage kidney disease secondary to type 2 diabetes mellitus and hypertension received a deceased by cardiac death kidney transplant. The patient's medical history included coronary artery disease and hyperlipidemia for which he was receiving rosuvastatin 40 mg daily. Five months after transplant, the patient developed BK viremia, which required multiple changes in immunosuppression and resulted in the initiation of leflunomide and cyclosporine modified. The patient used multiple pharmacies and coupon cards that delayed the identification of the DDIs between leflunomide, cyclosporine, and rosuvastatin. Approximately, 13 months after transplant, the biopsy report of the patient's allograft kidney showed acute cellular rejection Banff IB, hypertensive changes, and transplant glomerulopathy. This prompted the patient to receive a 3-day course of methylprednisolone 250 mg intravenous at the outpatient infusion center. Two weeks later, the patient presented to the transplant clinic with lightheadedness, dizziness, weakness, fatigue, bilateral eye drainage, and a decrease in appetite and was admitted to the hospital for further workup. On admission, creatine kinase was 2080 IU/L with myoglobin of 7601 ng/mL. The patient's diagnosis was statin myopathy with possible rhabdomyolysis acute kidney injury. Likely contributing factors included cyclosporine, leflunomide, and rosuvastatin DDI and administration of high-dose methylprednisolone. PRACTICE IMPLICATIONS: This case demonstrates the importance of pharmacist involvement throughout all phases of care in a kidney transplant recipient.

Clinical efficacy and safety of full-dose versus half-dose corticosteroids plus leflunomide for IgA nephropathy.

BACKGROUND: The results of leflunomide (LEF) in patients with IgA nephropathy (IgAN) were inconsistent. METHODS: A total of 149 kidney biopsy-confirmed IgAN patients with an estimated glomerular filtration rate (eGFR) ≥ 50 ml/min/1.73 m2 and protein excretion levels ≥0.75 g/d were enrolled, with 65 subjects receiving half-dose CS plus LEF (LEF group), and the 84 counterpart patients accepting full-dose corticosteroid (Full CS group). The primary outcomes included the complete remission (CR) rates and incidence of adverse events (AEs). The secondary outcomes were the overall remission (OR) rates and a combined event (eGFR reduced ≥30%, end-stage renal disease [ESRD], hemodialysis, peritoneal dialysis or kidney transplantation). RESULTS: During the 18 months of follow-up, the CR rates were 72 and 64% in the LEF and Full CS groups (P = 0.299), respectively. The proportion of patients with OR rates in the LEF group and Full CS group was 89% versus 75%, respectively (P = 0.027). Serious AEs were observed only in the Full CS group (P = 0.017). The incidences of total AEs (P = 0.036) and infections (P = 0.024) were lower in the LEF group than in the Full CS group. CONCLUSIONS: LEF combined with half-dose CS is superior to full-dose CS in the treatment of IgAN.

Effect of Half-Dose vs Stable-Dose Conventional Synthetic Disease-Modifying Antirheumatic Drugs on Disease Flares in Patients With Rheumatoid Arthritis in Remission: The ARCTIC REWIND Randomized Clinical Trial.

Importance: Sustained remission has become an achievable goal for patients with rheumatoid arthritis (RA) receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), but how to best treat patients in clinical remission remains unclear. Objective: To assess the effect of tapering of csDMARDs, compared with continuing csDMARDs without tapering, on the risk of flares in patients with RA in sustained remission. Design, Setting, and Participants: ARCTIC REWIND was a multicenter, randomized, parallel, open-label noninferiority study conducted in 10 Norwegian hospital-based rheumatology practices. A total of 160 patients with RA in remission for 12 months who were receiving stable csDMARD therapy were enrolled between June 2013 and June 2018, and the final visit occurred in June 2019. Interventions: Patients were randomly assigned to half-dose csDMARDs (n = 80) or stable-dose csDMARDs (n = 80). Main Outcomes and Measures: The primary end point was the proportion of patients with a disease flare between baseline and the 12-month follow-up, defined as a combination of Disease Activity Score (DAS) greater than 1.6 (threshold for RA remission), an increase in DAS score of 0.6 units or more, and at least 2 swollen joints. A disease flare could also be recorded if both the patient and investigator agreed that a clinically significant flare had occurred. A risk difference of 20% was defined as the noninferiority margin. Results: Of 160 enrolled patients (mean [SD] age, 55.1 [11.9] years; 66% female), 156 received the allocated therapy, of which 155 without any major protocol violations were included in the primary analysis population (77 receiving half-dose and 78 receiving stable-dose csDMARDs). Flare occurred in 19 patients (25%) in the half-dose csDMARD group compared with 5 (6%) in the stable-dose csDMARD group (risk difference, 18% [95% CI, 7%-29%]). Adverse events occurred in 34 patients (44%) in the half-dose group and 42 (54%) in the stable-dose group, none leading to study discontinuation. No deaths occurred. Conclusions and Relevance: Among patients with RA in remission taking csDMARD therapy, treatment with half-dose vs stable-dose csDMARDs did not demonstrate noninferiority for the percentage of patients with disease flares over 12 months, and there were significantly fewer flares in the stable-dose group. These findings do not support treatment with half-dose therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01881308.

Two-year cost-effectiveness of different COBRA-like intensive remission induction schemes in early rheumatoid arthritis: a piggyback study on the pragmatic randomised controlled CareRA trial.

OBJECTIVES: To evaluate the cost-effectiveness of treat-to-target strategies among recently diagnosed patients with rheumatoid arthritis (RA) using methotrexate (MTX) and a step-down glucocorticoid (GC) scheme (COBRA Slim) compared with (1) this combination with either sulphasalazine (COBRA Classic) or leflunomide (COBRA Avant-Garde) in high-risk patients and (2) MTX without GCs (Tight-Step-Up, TSU) in low-risk patients. METHODS: The incremental cost-utility was calculated from a healthcare perspective in the intention-to-treat population (n=379) of the 2-year open-label pragmatic randomised controlled Care in early RA trial. Healthcare costs were collected prospectively through electronic trial records. Quality-adjusted life years (QALYs) were estimated using mapping algorithms for EuroQoL-5 Dimension. Multiple imputation was used to handle missing data and bootstrapping to calculate CIs. Robustness was tested with biological disease-modifying antirheumatic drugs at biosimilar prices. RESULTS: In the high-risk group, Classic (∆k€1.464, 95% CI -0.198 to 3.127) and Avant-Garde (∆k€0.636, 95% CI -0.987 to 2.258) were more expensive compared with Slim and QALYs were slightly worse for Classic (∆-0.002, 95% CI -0.086 to 0.082) and Avant-Garde (∆-0.009, 95% CI -0.102 to 0.084). This resulted in the domination of Classic and Avant-Garde by Slim. In the low-risk group, Slim was cheaper (∆k€-0.617, 95% CI -2.799 to 1.566) and QALYs were higher (∆0.141, 95% CI 0.008 to 0.274) compared with TSU, indicating Slim dominated. Results were robust against the price of biosimilars. CONCLUSIONS: The combination of MTX with a GC bridging scheme is less expensive with comparable health utility than more intensive step-down combination strategies or a conventional step-up approach 2 years after initial treatment. TRIAL REGISTRATION NUMBER: NCT01172639.

BK virus encephalitis and end-stage renal disease in a child with hematopoietic stem cell transplantation.

BK virus encephalitis after HSCT is uncommon. Several reports of native kidney BKVN in patients with HSCT, hematologic malignancies, human immunodeficiency virus infection, and non-renal solid organ transplantation have been described. However, an uncommon combination of BK encephalitis and ESRD of native kidneys secondary to BK virus in a child with HSCT has not been described. We report a 10-year-old boy who presented with a gradually rising serum creatinine during treatment for severe autoimmune hemolytic anemia, which he developed 9 months after receiving an allogeneic HSCT for aplastic anemia. There was no proteinuria or hematuria present. Serum BK virus load was 5 × 106  copies/mL. A renal biopsy showed evidence of BKVN. He developed fever, seizures, and confusion, and the (CSF) showed significant presence of the BK virus (1 × 106  copies/mL) along with biochemical evidence of viral encephalitis. Cerebrospinal fluid cultures were negative. Despite significant clinical symptoms and presence of BK virus in CSF, the magnetic resonance brain imaging findings were minimal. With reduction of immunosuppression, there was resolution of BK encephalitis but BKVN remained resistant to multiple anti-BK virus agents, including leflunomide and cidofovir. He eventually became dialysis-dependent and, 6 years later, received a renal transplant from his mother. This case illustrates that BK virus in severely immunocompromised HSCT recipient may lead to BK encephalitis and BKVN of native kidneys, even without hemorrhagic cystitis, leading to ESRD. Knowledge of such is important for appropriate timely evaluation and management.

Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2.

Rheumatoid arthritis patients can be prescribed a combination of immunosuppressive drug leflunomide (LEF) and the antiviral drug acyclovir to reduce the high risk of infection. Acyclovir is a substrate of organic anion transporter (OAT) 1/3 and multidrug resistance-associated protein (MRP) 2. Considering the extraordinarily long half-life of LEF's active metabolite teriflunomide (TER) and the kidney injury risk of acyclovir, it is necessary to elucidate the potential impact of LEF on the disposition of acyclovir. Here we used a specific MRP inhibitor MK571 and probenecid (OAT1/3 and MRP2 inhibitor) to assess the effects of MRP2 and OAT1/3 on the pharmacokinetics and tissue distribution of acyclovir in rats. We showed that LEF and probenecid, but not MK571 significantly increased the plasma concentration of acyclovir. However, kidney and liver exposures of acyclovir were increased when coadministered with LEF, probenecid or MK571. The kidney/plasma ratio of acyclovir was increased to approximately 2-fold by LEF or probenecid, whereas it was increased to as much as 14.5-fold by MK571. Consistently, these drugs markedly decreased the urinary excretion of acyclovir. TER (0.5-100 µmol/L) dose-dependently increased the accumulation of acyclovir in MRP2-MDCK cells with an IC50 value of 4.91 µmol/L. TER (5 µmol/L) significantly inhibited the uptake of acyclovir in hOAT1/3-HEK293 cells. These results suggest that LEF/TER increased the kidney accumulation of acyclovir by inhibiting the efflux transporter MRP2, which increased its kidney/plasma ratio and renal injury risk. However, the inhibitory effects of LEF/TER on OAT1/3 reduced the tubular cells' uptake of acyclovir and increased the plasma concentration.

Use of Leflunomide for Treatment of Cytomegalovirus Infection in Recipients of Allogeneic Stem Cell Transplant.

Cytomegalovirus (CMV) reactivations are common after allogeneic stem cell transplants, and pre-emptive therapy has been found to be effective. However, in India, treatment options are limited because of high cost and toxicity of ganciclovir and unavailability of cidofovir and foscarnet. Leflunomide is a cheap and easily available anti-rheumatoid arthritis drug that has been shown to have anti-CMV properties both in vitro and in vivo. It also has been used effectively for CMV reactivation after renal transplants. In this retrospective analysis, we analyzed 70 allogeneic stem cell transplants that were conducted between April 2015 and February 2017. There were 49 episodes of CMV reactivations in 43 patients in this period. Leflunomide was used in 24 episodes. It was effective in CMV clearance in 9 of the 24 episodes (38%). When the CMV copy number was <2 × 103 copies/mL, leflunomide was effective in 9 of 17 (53%) episodes, but when the copy number was >2 × 103, leflunomide was ineffective in all of the 7 episodes. This difference was statistically significant (P= .022 by Fisher exact test), suggesting that leflunomide may be more effective in clearance of CMV when copy numbers are low.

Effectiveness of different combinations of DMARDs and glucocorticoid bridging in early rheumatoid arthritis: two-year results of CareRA.

OBJECTIVES: To investigate whether MTX should be combined with an additional DMARD and bridging glucocorticoids as initial treatment for patients with early RA to induce an effective long-term response. METHODS: The Care in early RA study is a two-year investigator-initiated pragmatic multicentre randomized trial. Early RA patients, naïve to DMARDs and glucocorticoids, were stratified based on prognostic factors. High-risk patients were randomized to COBRA-Classic (n = 98): MTX, sulfasalazine, prednisone step-down from 60 mg; COBRA-Slim (n = 98): MTX, prednisone step-down from 30 mg; or COBRA-Avant-Garde (n = 93): MTX, leflunomide, prednisone step-down from 30 mg. Low-risk patients were randomized to COBRA-Slim (n = 43); or Tight Step Up (TSU) (n = 47): MTX without prednisone. Clinical/radiological outcomes at year 2, sustainability of response, safety and treatment adaptations were assessed. RESULTS: In the high-risk group 71/98 (72%) patients achieved a DAS28-CRP < 2.6 with COBRA-Slim compared with 64/98 (65%) with COBRA-Classic and 69/93 (74%) with COBRA-Avant-Garde (P = 1.00). Other clinical/radiological outcomes and sustainability of response were similar. COBRA-Slim treatment resulted in less therapy-related adverse events compared with COBRA-Classic (P = 0.02) or COBRA-Avant-Garde (P = 0.005). In the low-risk group, 29/43 (67%) patients on COBRA-Slim and 34/47 (72%) on TSU achieved a DAS28-CRP < 2.6 (P = 1.00). On COBRA-Slim, low-risk patients had lower longitudinal DAS28-CRP scores over 2 years, a lower need for glucocorticoid injections and a comparable safety profile compared with TSU. CONCLUSION: All regimens combining DMARDs with glucocorticoids were effective for patients with early RA up to 2 years. The COBRA-Slim regimen, MTX monotherapy with glucocorticoid bridging, provided the best balance between efficacy and safety, irrespective of patients' prognosis. TRIAL REGISTRATION: ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT01172639.

Leflunomide therapy for refractory cytomegalovirus infections in hematopoietic stem cell transplant recipients.

BACKGROUND: Currently, there are no prospective, randomized trials analyzing leflunomide for the treatment of cytomegalovirus infection or disease in allogeneic stem cell transplant patients. OBJECTIVE: The primary objective of this case series was to determine the clinical and virological responses of utilizing leflunomide as therapy for refractory cytomegalovirus infections, unresponsive to first-line therapy in allogeneic stem cell transplant patients. Additionally, patient and leflunomide specific characteristics were identified and determined in this descriptive case series. METHODS: This is a single-center, case series of adult allogeneic stem cell transplant patients with refractory cytomegalovirus infections receiving leflunomide between 1 January 2005 and 31 March 2015. RESULTS: A total of 14 patients with refractory cytomegalovirus infections received leflunomide. All patients received concurrent anti-cytomegalovirus therapy. Nine of 13 patients tested positive for phosphotransferase UL97 and/or viral DNA polymerase UL54 genotype mutations. Nine patients achieved a virological response with undetectable cytomegalovirus titers. Of the 13 patients with teriflunomide serum levels, eight patients maintained levels >40 micrograms/milliliter (mcg/mL). Common adverse effects were pancytopenia (n = 8) and elevated liver function tests (n = 4). CONCLUSIONS: Despite current strategies, refractory or recurrent cytomegalovirus infection and disease remain a clinical challenge to treat in the stem cell transplant patient population. Leflunomide used in combination with other concomitant therapies use for refractory cytomegalovirus infection in clinical practice may be a safe and effective option in the allogeneic stem cell transplant patient population.

Intra-articular leflunomide-loaded poly(ε-caprolactone) implants to treat synovitis in rheumatoid arthritis.

Rheumatoid arthritis is an autoimmune pathology that manifests as chronic inflammatory arthropathy and synovitis. Treatment of rheumatoid arthritis is based on the administration of different types of drugs, including leflunomide, an antirheumatic drug. However, the long-term systemic use of leflunomide may be associated with adverse effects. Local therapy could be an efficient strategy to treat synovitis triggered by rheumatoid arthritis without inducing adverse effects. In this study, leflunomide-loaded poly(ε-caprolactone) implants (leflunomide PCL implants) were evaluated as local drug delivery systems capable of attenuating inflammation and angiogenesis, which represent events of synovitis. Leflunomide PCL implants were designed by hot molding technique; and they were characterized by FTIR and DSC. These analytical techniques demonstrated the chemical integrity and dispersion of drug into the polymeric chains. Then, a spectrophometric method was developed and validated to quantify the leflunomide incorporated into the PCL implants and released from them. Linearity was obtained by ordinary least squares regression method to estimate the linear regression equation. Residues were evaluated considering normality, independence and homoscedasticity. Precision was lower than 5 %, and accuracy ranged from 98 to 104.5 %. Quantitation limit was 2.0 µg mL-1. PCL implants provided controlled and sustained release of leflunomide for 30 consecutive days after inserting these systems in the subcutaneous tissue of mice. The main mechanisms of drug delivery were solubilization and diffusion from polymer. Then, a non-biocompatible sponge was inserted into the subcutaneous tissue of mice to function as a frame to develop the inflammatory and angiogenic processes. Leflunomide PCL implants were inserted in direct contact with the sponge. At 4, 7 and 10 days after-sponge implantation, the key components of inflammatory angiogenesis were measured to verify the regression of these events induced by drug. Leflunomide controlled released from polymeric implants downregulated the neutrophil and monocyte/macrophage infiltration due to the reduced expression of myeloperoxidase (MPO) and N-acetyl-ß-d-glucosaminidase (NAG), respectively. As the influx of these pro-inflammatory cells was modulated by leflunomide, the production of nitric oxide (NO), a pro-inflammatory substance, reached low concentrations in the sponge. As a consequence of the modulation of inflammation at the pathological site, the angiogenic process was downregulated, since the hemoglobin levels in the sponge were drastically reduced. The accumulation of leflunomide in the pathological site did not induce nephrotoxicity or hepatototoxicity, as confirmed by histological analyses. Finally, intra-articular leflunomide PCL implants represent a potential therapeutic alternative to treat locally the synovitis triggered by rheumatoid arthritis without inducing systemic adverse effects.

Sustained Drug Treatment Alters the Gut Microbiota in Rheumatoid Arthritis.

Several studies have investigated the causative role of the microbiome in the development of rheumatoid arthritis (RA), but changes in the gut microbiome in RA patients during drug treatment have been less well studied. Here, we tracked the longitudinal changes in gut bacteria in 22 RA patients who were randomized into two groups and treated with Huayu-Qiangshen-Tongbi formula (HQT) plus methotrexate (MTX) or leflunomide (LEF) plus MTX. There were differences in the gut microbiome between untreated (at baseline) RA patients and healthy controls, with 37 species being more abundant in the RA patients and 21 species (including Clostridium celatum) being less abundant. Regarding the functional analysis, vitamin K2 biosynthesis was associated with RA-enriched bacteria. Additionally, in RA patients, alterations in gut microbial species appeared to be associated with RA-related clinical indicators through changing various gut microbiome functional pathways. The clinical efficacy of the two treatments was further observed to be similar, but the response trends of RA-related clinical indices in the two treatment groups differed. For example, HQT treatment affected the erythrocyte sedimentation rate (ESR), while LEF treatment affected the C-reactive protein (CRP) level. Further, 11 species and 9 metabolic pathways significantly changed over time in the HQT group (including C. celatum, which increased), while only 4 species and 2 metabolic pathways significantly changed over time in the LEF group. In summary, we studied the alterations in the gut microbiome of RA patients being treated with HQT or LEF. The results provide useful information on the role of the gut microbiota in the pathogenesis of RA, and they also provide potentially effective directions for developing new RA treatments.

Precision Medicine With Leflunomide: Consideration of the DHODH Haplotype and Plasma Teriflunomide Concentration and Modification of Outcomes in Patients With Rheumatoid Arthritis.

OBJECTIVE: Leflunomide is a commonly used disease-modifying drug in the treatment of rheumatoid arthritis (RA). Its effects are mediated via inhibition of dihydroorotate dehydrogenase (DHODH) by its active metabolite teriflunomide, and the pharmacokinetics of teriflunomide are highly variable. Our objective was to examine the association between the DHODH haplotype and plasma teriflunomide concentration with response to leflunomide in patients with RA where leflunomide was added to an existing disease-modifying drug regimen after failure to achieve an adequate response with conventional triple therapy. METHODS: Patients with RA who were taking, or were about to initiate, leflunomide were included. Participant characteristics, including the DHODH haplotype, were determined. Up to 5 plasma samples were collected after leflunomide was initiated for assays of total and free teriflunomide concentration. Disease activity was determined via the 28-joint Disease Activity Score (DAS28). The association between DAS28 scores and patient covariates was determined by linear mixed-effects modeling. RESULTS: A total of 67 patients were included in the study. The DAS28 score after initiation of leflunomide was associated with the baseline DAS28 score (ß = 0.70, P < 0.001) and was higher in those who carried the DHODH haplotype 2 (ß = 0.56. P = 0.01) and did not carry the shared epitope (ß = 0.56, P = 0.013). As total and free plasma teriflunomide concentration increased, the DAS28 score was significantly lower (P < 0.001 and P = 0.001, respectively). When considering threshold concentrations, teriflunomide concentrations >16 mg/liter were associated with a DAS28 score that was 0.33 lower, and when free teriflunomide concentration was >35 µg/liter, the DAS28 score was 0.32 lower. CONCLUSION: Teriflunomide concentration and carriage of the DHODH haplotype 2 are associated with response to leflunomide in patients with RA, and a total plasma teriflunomide concentration of at least 16 mg/liter is needed to maximize the likelihood of response.

Leflunomide monotherapy versus combination therapy with conventional synthetic disease-modifying antirheumatic drugs for rheumatoid arthritis: a retrospective study.

Leflunomide (LEF) is a conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for the treatment of rheumatoid arthritis. However, there are few reports on the comparison of efficacy between LEF alone and combined with other csDMARDs. Here, the efficacy and safety of LEF monotherapy (88) and combination (361) therapy groups were evaluated. After 3 months, there were no significant differences in 28-joint disease activity score (DAS28), health assessment questionnaire (HAQ), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) between the monotherapy and combination groups (all P > 0.05). According to the European League Against Rheumatism (EULAR) response criteria, it was found that the DAS28 response rates were similar in the two groups (P > 0.05). Besides, the two groups presented similar safety profiles. Subgroup analysis found that there was no difference in efficacy among the three combined therapies (LEF + methotrexate (MTX), LEF + hydroxychloroquine (HCQ), and LEF + MTX + HCQ) and LEF monotherapy. Furthermore, when the dose of LEF was less than 40 mg/day, no significant difference in efficacy was observed between low and high doses. Overall, these results indicated that low dose LEF monotherapy was not inferior to the combination therapy.

Efficacy and Safety of Combined Therapy With Synthetic Disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis: Systematic Literature Review. / Eficacia y seguridad de la terapia combinada con fármacos modificadores de la enfermedad sintéticos en la artritis reumatoide: revisión sistemática de la literatura.

OBJECTIVE: 1) To systematically and critically review the evidence of combined therapy with synthetic disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA); 2) To design practical recommendations on their use. METHODS: A systematic literature review (SLR) was performed with a sensitive bibliographic search strategy in Medline, EMBASE and Cochrane Library. We selected randomized clinical trials that analyzed the efficacy and/or safety of 1) combined therapy of synthetic compared with sequential therapy of synthetic DMARD in early RA; and 2) combination of methotrexate+leflunomide or triple therapy with synthetic DMARD in established RA refractory to synthetic DMARD. Two reviewers made the first selection by title and abstract and 11 performed the selection after detailed review of the articles and data collection. The quality of the studies was evaluated with the Jadad scale. Based on the results, related recommendations were agreed upon in a nominal group meeting. RESULTS: Ultimately, no articles were included in the SLR. The analysis of the reviewed articles demonstrated the effectiveness of the treatment with synthetic DMARD following a "treat to target" strategy in early RA patients, and of combination therapy of synthetic DMARD in established RA refractory to synthetic DMARD. This resulted in 6 recommendations concerning combination therapy with synthetic DMARD. CONCLUSIONS: These recommendations aim to facilitate decision-making with the use of combined therapy with DMARD in RA.

Comparing methotrexate monotherapy with methotrexate plus leflunomide combination therapy in psoriatic arthritis: protocol of a randomized, placebo-controlled, double-blind clinical trial (COMPLETE-PsA).

BACKGROUND: Both methotrexate (MTX) and leflunomide (LEF) are registered and regularly prescribed as first-line treatments for the use in patients with psoriatic arthritis (PsA) and they are occasionally used in combination. However, evidence about their individual, and especially combined efficacy, in PsA is lacking. The aim of this study is to compare the effectiveness and safety of MTX and LEF combination therapy to MTX monotherapy in patients with PsA. METHODS: COMPLETE-PsA is a randomized, placebo-controlled, double-blind clinical trial. Disease-modifying antirheumatic drug (DMARD)-untreated patients (n = 78) with clinical diagnosis of active (i.e. ≥2 swollen joints) PsA will be randomized 1:1 (stratified for high disease activity, Psoriatic Arthritis Disease Activity Score [PASDAS] ≥ 5.4) to the combination or monotherapy. The intervention group receives MTX 25 mg (oral or subcutaneous) once weekly plus LEF 20 mg daily, and the control group receives the same but with placebo instead of LEF daily. Primary endpoint is between-group difference in PASDAS at 16 weeks, adjusted for baseline PASDAS. Key secondary parameters include between-group comparisons in change in Disease Activity in Psoriatic Arthritis (DAPSA) score, skin score, enthesitis score, dactylitis score, and swollen/tender joint count, as well as the proportion of patients fulfilling minimal disease activity (MDA), American College of Rheumatology (ACR) 20/50/70 response criteria at week 16. Furthermore, safety, function and quality of life (Health Assessment Questionnaire [HAQ], Psoriatic Arthritic Impact of Disease [PSAID], Short Form 12 [SF-12]) will be assessed. DISCUSSION: This is, to our knowledge, the first randomized, placebo-controlled, double-blind clinical trial assessing the effectiveness of MTX and LEF combination therapy in patients with PsA. The study will provide important information for treatment strategies and treatment recommendations. TRIAL REGISTRATION: Dutch Trial Register NTR7632 (3 December 2018). CMO NL66544.091.18 (19 November 2018).

A Small-Scale Medication of Leflunomide as a Treatment of COVID-19 in an Open-Label Blank-Controlled Clinical Trial.

We recently reported that inhibitors against human dihydroorotate dehydrogenase (DHODH) have broad-spectrum antiviral activities including their inhibitory efficacies on SARS-CoV-2 replication in infected cells. However, there are limited data from clinical studies to prove the application of DHODH inhibitors in Coronavirus disease 2019 (COVID-19) patients. In the present study, we evaluated Leflunomide, an approved DHODH inhibitor widely used as a modest immune regulator to treat autoimmune diseases, in treating COVID-19 disease with a small-scale of patients. Cases of 10 laboratory-confirmed COVID-19 patients of moderate type with obvious opacity in the lung were included. Five of the patients were treated with Leflunomide, and another five were treated as blank controls without a placebo. All the patients accepted standard supportive treatment for COVID-19. The patients given Leflunomide had a shorter viral shedding time (median of 5 days) than the controls (median of 11 days, P = 0.046). The patients given Leflunomide also showed a significant reduction in C-reactive protein levels, indicating that immunopathological inflammation was well controlled. No obvious adverse effects were observed in Leflunomide-treated patients, and they all discharged from the hospital faster than controls. This preliminary study on a small-scale compassionate use of Leflunomide provides clues for further understanding of Leflunomide as a potential antiviral drug against COVID-19.

Switching to secukinumab in difficult-to-treat psoriasis recalcitrant to methotrexate, cyclosporine and leflunomide, in a tuberculosis-endemic country.

Several biological agents have been approved for the treatment of recalcitrant psoriasis. However, there is a lack of a consensus algorithm guiding the drug selection for patients who have failed conventional drugs. In cases not improving with cyclosporine, direct switching to a biological therapy usually leads to a disease flare owing to increased production of interleukin (IL)-17A. Thus, secukinumab, a rapidly acting anti-IL-17A drug, may be ideal in such situations.

Effect of adjuvant therapy with electroacupuncture on bone turnover markers and interleukin 17 in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the effect of electroacupuncture as an adjuvant treatment with first-line medications on bone metabolism biomarkers and interleukin-17 (IL-17) in the peripheral blood of patients with rheumatoid arthritis (RA). METHODS: Sixty RA patients were randomized into three groups. The control group was treated with methotrexate plus leflunomide (MTX+LEF), the acupuncture group was treated with simple needling plus MTX + LEF, and the patients in the electroacupuncture (EA) group were treated with EA plus MTX + LEF. EA or acupuncture was applied every other day for a total of 10 times over a treatment period of 8 weeks. RESULTS: In all three treatment groups, serum levels of the bone metabolism markers PICP, N-MID, and B-ALP were elevated and the concentrations of the inflammatory markers ß-CTx, IL-17, CRP, and TRACP-5b were reduced after treatment. These differences were significant for the EA group but not the other groups (P < 0.05). CONCLUSION: EA could effectively reduce the suffering and improve the quality of life of RA patients. It is a promising adjuvant therapy for enhancing the effectiveness of clinical therapeutics.