Efficacy and Safety of Azathioprine during Remission of Immune-Mediated Thrombotic Thrombocytopenic Purpura

Introduction Acquired immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening thrombotic microangiopathy caused by the development of anti-ADAMTS13 autoantibodies. Up to 50% of patients surviving an acute iTTP event experience one or more relapses. Recent guidelines suggest treatment with rituximab in clinical remission in iTTP patients with low ADAMTS13 activity to prevent acute iTTP relapses. A 10% of cases who do not respond to rituximab or develop allergic reactions requiring therapy discontinuation have been reported. In these patients, azathioprine might be an alternative treatment to prevent acute iTTP relapses. The aim of this study was to assess the efficacy and safety of azathioprine treatment in iTTP patients in clinical remission. Methods We designed a retrospective cohort study including all iTTP patients treated with azathioprine during clinical remission, enrolled in the Milan TTP Registry between May 2003 and October 2020 and followed for at least six months. The efficacy of azathioprine was assessed in patients with at least four weeks of treatment. The primary outcome was clinical relapse during azathioprine treatment. The secondary outcomes were the partial and complete responses of ADAMTS13 (an ADAMTS13 activity increase above 20% and 45%, respectively) in patients with ADAMTS13 activity below 20% before azathioprine start. ADAMTS13 relapse (an ADAMTS13 activity decrease below 20%) in patients with a prior ADAMTS13 response was also assessed. As for the safety analysis, adverse events (AEs), associated or not with treatment discontinuation, were retrieved from clinical charts of all patients. Lastly, we assessed the association between variables such as sex, age, and concomitant autoimmune diseases, and ADAMTS13 response, using logistic regression models. Results We enrolled 43 patients with iTTP treated with azathioprine during clinical remission (Table 1). Forty-two percent of the patients had at least one concomitant autoimmune disease. The median exposure to azathioprine was 16 months (interquartile range [IQR] 8-49 months), the median dosage 1.3 mg/kg/day (IQR 0.9-1.6 mg/kg/day). Thirty-five cases were available for the primary outcome analysis (Table 2). Seven patients relapsed after a median time of 14 months after azathioprine start (IQR 8-58 months). The cumulative incidence of clinical relapse during azathioprine treatment was 10% at 1 year (95% Confidence Interval [CI] 0-21%), 22% at 2 years (95% CI 6-38%). Twenty-one cases were available for the secondary outcomes analysis. An ADAMTS13 partial response occurred in 10 patients (48%), after a median time of 3 months (IQR 3-9 months) after azathioprine start and lasted for a median time of 40 months (IQR 16-56 months). An ADAMTS13 complete response was achieved in 33% of patients, after a median time of 8 months (IQR 3-16 months) after azathioprine start and lasted for a median time of 16 months (IQR 0-53 months). Of the 10 responders, 3 (30%) had a subsequent ADAMTS13 relapse at 22, 24 and 37 months after azathioprine start. Adverse events were observed in 30% of patients, after a median time of 50 days after azathioprine start (IQR 26-331 days). Liver and pancreas alterations with increased levels of ALT, AST, GGT, ALP and lipase were the most frequent, followed by nausea and leukopenia (Table 3). In one patient, acute myeloid leukemia was diagnosed 6 months after azathioprine start. Fifteen percent of the patients had to stop the treatment due to AEs. No demographic or anamnestic variables were associated with ADAMTS13 response to azathioprine. Conclusions Forty-eight percent of patients attained an ADAMTS13 activity above 20%, with a durable response lasting more than 3 years, while adverse events were generally mild in nature. Azathioprine could be a valid and safe alternative in case of ineligibility or failure to respond to rituximab. Figure 1 Figure 1. Disclosures Mancini: Instrumentation Laboratory, Sanofi: Honoraria. Peyvandi: Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria. OffLabel Disclosure: Azathioprine. It is an immunosuppressive drug used for the prevention of rejection in renal homotransplantation and for treatment of active rheumatoid arthritis.

Chronic recurrent multifocal osteomyelitis of the left femur associated with ulcerative colitis: a case report

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare condition characterized by chronic relapsing noninfectious bone inflammation of unknown etiology. Although CRMO is considered an extraintestinal manifestation in patients with inflammatory bowel disease, most cases of CRMO are associated with Crohn’s disease; very few are associated with ulcerative colitis (UC). We herein describe a 21-year-old patient with UC who developed recurrent left thigh pain. The patient was diagnosed with CRMO associated with UC, which was well controlled with azathioprine treatment.

AIRE Gene Mutation Presenting at Age 2 Years With Autoimmune Retinopathy and Steroid-Responsive Acute Liver Failure: A Case Report and Literature Review

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare monogenic autosomal recessive disorder caused by mutation in the autoimmune regulator (AIRE) gene. Patients usually are diagnosed at ages between 5 and 15 years when they show 3 or more manifestations, most typically mucocutaneous candidiasis, Addison’s disease, and hypoparathyroidism. APECED-associated hepatitis (APAH) develops in only 10% to 40% of patients, with severity varying from subclinical chronic active hepatitis to potentially fatal acute liver failure (ALF). Ocular abnormalities are fairly common, most often keratopathy but sometimes retinopathy. Here we report a 2-year-old Japanese girl with an AIRE gene mutation who developed APAH with ALF, preceded by autoimmune retinopathy associated with anti-recoverin antibody before major symptoms suggested a diagnosis of APECED. Intravenous pulse methylprednisolone therapy followed by a corticosteroid combined with azathioprine treatment resolved ALF and achieved control of APAH. To our knowledge, our patient is the youngest reported to have ALF resulting from an AIRE gene mutation. Pulse methylprednisolone induction therapy followed by treatment with corticosteroid plus azathioprine may well be effective in other children with APAH and AIRE gene mutations.

Azathioprine Treatment in Systemic Lupus Erythematosus: A Double Edged Sword

Extremely severe pancytopenia induced by low dosage of azathioprine in systemic lupus erythematosus patients is rare. A 40-year-old Chinese female was diagnosed with systemic lupus erythematosus. She suffered worse erythema, oral ulceration, raised erythrocyte sedimentation rate and high anti-dsDNA in August 2013. Then she was initiated on oral azathioprine 50mg/d and extremely severe pancytopenia was seen in September 2013. She was recovered by a series of treatments. Regular monitoring of blood counts is highly recommended to reduce the possible serious myelosuppression induced by azathioprine.

NUDT15 genotyping during azathioprine treatment in patients with inflammatory bowel disease: implications for a dose-optimization strategy

Background NUDT15 R139C is an Asian-prevalent genetic variant related to azathioprine (AZA) intolerance in patients with inflammatory bowel disease (IBD). However, it remains unclear how to utilize the genotyping results to improve the step-up dosing strategy with an already low starting dose in Asian practice. Methods Clinical data of eligible IBD patients who received AZA therapy and NUDT15 R139C testing were retrospectively collected. The relationship between NUDT15 genotype, AZA doses, and AZA-induced toxicity and efficacy were comprehensively analysed. Results A total of 159 patients were included for toxicity analysis. Compared with the wild genotype, patients heterozygous for R139C are more prone to developing myelotoxicity and alopecia (P = 0.007; P = 0.042). In particular, they had a 5.4-fold risk of developing myelotoxicity when AZA dosage was increased from 25 mg/d to 50 mg/d (P < 0.001). Regarding efficacy, 115 patients who had received AZA for >4 months and maintained clinical remission on AZA monotherapy were included for further analysis. R139C heterozygotes were finally titrated to a significantly lower dose than the wild genotype [median (interquartile range): 0.83 (0.75–0.96) vs 1.04 (0.89–1.33) mg/kg/d, P = 0.001], whereas the clinical remission rates did not differ between groups (P = 0.88). Conclusions IBD patients with R139C heterozygote are highly susceptible to AZA-induced myelotoxicity at an escalated dose of 50 mg/d. Thus, they may require a smaller dose increase after a starting dose of 25 mg/d. The final target dose of these patients could be set lower than that of the wild genotypes without compromising efficacy.

Lupus Disease with Lupus Nephritis - 14 Years of Clinical-Biological Observations

We present the case of a female patient diagnosed in 2004 with systemic lupus erythematosus, initially with joint and hematological damage complaint, for which she was treated with Methylprednisolone for 6 months. Subsequently, symptomatology and paraclinical screening raised the suspicion of renal impairment, a pulse therapy with Solumedrol and Cyclophosphamide was initiated, a total of 6 pulses. She is in the database of our Clinic since March 2008, when a renal biopsy was performed, revealing a class IV lupus nephritis, initiating treatment with Mycophenolate mofetil and Prednisone until 2010, when the dose of Prednisone is progressively reduced until cessation at the time of remission. Subsequently she presented two relapse episodes, recovered by pulse therapy with Methylprednisolone and Cyclophosphamide, followed by maintenance therapy with Mycophenolate mofetil and Prednisone with a good clinical evolution. In 2017 the patient has a pregnancy with favorable evolution (under treatment with Azathioprine), presenting normal values of cDNA, C3, C4 during the 9 months, but with a persistent nephrotic-range proteinuria; in these conditions gives birth physiologically at 37 weeks. During 2019 apparent remission is maintained (stationary nitrogen retention, anti-dsDNA antibodies within normal range), but with moderate anaemia and persistent, but diminished proteinuria (being under treatment with reduced dose Prednisolone and Mycophenolate mofetil); along the way proteinuria is accentuated again and it is decided to return to reduced dose Azathioprine treatment, with good clinical evolution.Conclusion. The presented case reinforces the idea of systematic monitoring of patients with SLE and the need for permanent adaptation of treatment especially when there is an increased risk of relapse. Pregnancy, paradoxically well tolerated, increases subsequently the risk of reactivation of lupus nephritis.