A Novel Case of Leflunomide-Induced Thrombotic Thrombocytopenic Purpura

Shields, Morgan C.; Skelton, William Paul; Laber, Damian A.; Verbosky, Michael; Ashraf, Noman

doi:10.14740/jh837

Cited by 3 publications

(2 citation statements)

References 12 publications

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“…One (10%, n = 10) patient was still actively taking caplacizumab. One patient discontinued caplacizumab after 8 days due to normalization of ADAMTS13 activity following the discontinuation of leflunomide [ 16 ].…”

Section: Resultsmentioning

confidence: 99%

Post Approval Experience with Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura at a Single Institution

Logothetis

Patel

Eatrides

et al. 2021

JCM

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Caplacizumab prevents platelet adhesion and has been approved for acquired thrombotic thrombocytopenic purpura (aTTP). This study was retrospective, including all patients diagnosed with aTTP and treated with caplacizumab since commercial availability in 2019 until 28 February 2021 at a single academic hospital with no exclusion criteria. Results used definitions for outcomes in aTTP from the International Working Group Consensus. Ten patients with aTTP received caplacizumab. The median age was 52 years. Six (60%) patients had refractory aTTP while 4 (40%) had newly diagnosed aTTP. The median laboratory values prior to therapy demonstrated: platelet count (PC) 29/uL, LDH 518 U/L (182–1850), ADAMTS13 activity 3% and ADAMTS13 inhibitor 1.4 BU. Everyone received glucocorticoids, rituximab, therapeutic plasma exchange (TPE) and caplacizumab. The median number of TPE was 12 days. Caplacizumab was started at a median of 5 days after the first TPE and the median treatment duration was 31 days. Normalization of PC, LDH and ADAMTS13 activity in days were 5, 3.5, and 32.5, respectively. Six (60%) patients achieved complete response, 3 (30%) had refractory disease and 1 (10%) had relapsed aTTP. No subject suffered abnormal bleeding, or thrombotic event. There were no deaths. Caplacizumab with TPE, glucocorticoids and rituximab was a safe and effective therapy for aTTP.

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Section: Resultsmentioning

confidence: 99%

Post Approval Experience with Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura at a Single Institution

Logothetis

Patel

Eatrides

et al. 2021

JCM

Self Cite

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“…LEFN is completely metabolized into teriflunomide (A-771726): an active metabolite in the liver and gut mucosa [ 2 ]. LEFN has been proven to induce hepatotoxicity, anaphylaxis, toxic epidermal necrolysis, Stevens–Johnson syndrome, and pulmonary effects [ 3 , 4 , 5 , 6 , 7 ]. Additionally, hepatotoxicity induced by LEFN was linked to mitochondrial dysfunction at the transcript level [ 8 ], oxidative stress [ 9 , 10 ], and unfolded proteins accumulation [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

The Anti-Rheumatic Drug, Leflunomide, Induces Nephrotoxicity in Mice via Upregulation of TGFβ-Mediated p53/Smad2/3 Signaling

Aljohani

Alqarni

Alrashidi

et al. 2022

Toxics

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Recent studies indicated renal toxicity and interstitial nephritis in patients receiving leflunomide (LEFN), but the exact mechanism is still unknown. The transforming growth factor β (TGFβ)/p53/Smad2/3 pathway crucially mediates renal fibrosis. We aimed to assess the nephrotoxic effect of LEFN in mice and the possible role of TGFβ-stimulated p53/SMAD2/3 signaling. The study design involved distributing sixty male albino mice into four groups: (i) vehicle-treated mice, (ii) LEFN (2.5 mg/kg), (iii) LEFN (5 mg/kg), and (iv) LEFN (10 mg/kg). The drug was given orally every 48 h and continued for 8 weeks. Blood samples were then taken from mice for the determination of kidney function parameters. Right kidneys were used for histopathologic staining and immunohistochemistry, whereas left kidneys were frozen and used for Western blot analysis of the target proteins, p-p53 and Smad2/3. Results indicated that chronic administration of LEFN in mice resulted in a four- and nine-fold increase in serum urea and creatinine levels, respectively. Kidney specimens stained with hematoxylin and eosin or periodic acid–Schiff showed significant histopathological manifestations, such as cellular irregularity, interstitial congestion, and moderate lymphocytic inflammatory infiltrate in mice treated with LEFN. Western blotting indicated upregulation of the p-p53/Smad2/3 proteins. LEFN, especially in the highest dose (10 mg/kg), produced prominent nephrotoxicity in mice. This toxicity is mediated through stimulating fibrotic changes through TGFβ-stimulated p53/Smad2/3 signaling and induction of glomerular and tubular apoptosis. An improved understanding of LEFN-induced nephrotoxicity would have great implications in the prediction, prevention, and management of leflunomide-treated rheumatic patients, and may warrant further clinical studies for following up these toxidromes.

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Drug‐induced thrombotic thrombocytopenic purpura: A systematic review and review of European and North American pharmacovigilance data

et al. 2022

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Summary Many medications have been reported to be associated with thrombotic thrombocytopenic purpura (TTP) through pharmacovigilance data and published case reports. Whilst there are existing data available regarding drug‐induced thrombotic microangiopathy, there is no available synthesis of evidence to assess drug‐induced TTP (DI‐TTP). Despite this lack of evidence, patients with TTP are often advised against using many medications due to the theoretical risk of DI‐TTP. This systematic review evaluated the evidence for an association of medications reported as potential triggers for TTP. Of 5098 records available 261 articles were assessed further for eligibility. Fifty‐seven reports, totalling 90 patients, were included in the final analysis. There were no cases where the level of association was rated as definite or probable, demonstrating a lack of evidence of any drug causing DI‐TTP. This paucity of evidence was also demonstrated in the pharmacovigilance data, where 613 drugs were reported as potential causes of TTP without assessment of the strength of association. This systematic review demonstrates the need for standardised reporting of potential drugs causing TTP. Many reports omit basic information and, therefore, hinder the chance of finding a causative link if one exists.

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A Novel Case of Leflunomide-Induced Thrombotic Thrombocytopenic Purpura

Cited by 3 publications

References 12 publications

Post Approval Experience with Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura at a Single Institution

Post Approval Experience with Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura at a Single Institution

The Anti-Rheumatic Drug, Leflunomide, Induces Nephrotoxicity in Mice via Upregulation of TGFβ-Mediated p53/Smad2/3 Signaling

Drug‐induced thrombotic thrombocytopenic purpura: A systematic review and review of European and North American pharmacovigilance data

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