Azathioprine Maintenance Therapy Research Articles

Head-to-head studies on connective tissue diseases and vasculitides

Head-to-head (H2H) studies enable the direct comparison of several alternative therapeutic approaches and thus provide the evidence-based foundation for the relative position of one treatment as compared to others for a specific indication. These trials constitute an important addition to placebo-controlled clinical trials. Among the controlled clinical trials not performed by the pharmaceutical industry, there are arelevant number of H2H trials for connective tissue diseases (CTDs) and vasculitides, particularly for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This article encompasses a review of the H2H trials for CTDs and vasculitides and discusses their relevance for current treatment algorithms. For SLE the H2H trials were predominantly performed for the treatment of lupus nephritis, demonstrating the impact of low-dose cyclophosphamide and mycophenolate as well as azathioprine for maintenance therapy. In recent H2H trials rituximab could be established as induction and maintenance therapy for AAV, which has now been incorporated into current treatment guidelines. Further comparative trials will be necessary in order to select the most effective and safest treatment for every patient, in the sense of personalized medicine.

Human leukocyte antigen association with azathioprine-induced drug hypersensitivity reactions in patients with anti-neutrophil cytoplasmic antibody associated vasculitis

Azathioprine (AZA) drug hypersensitivity reaction (DHR) is an uncommon yet potentially lethal condition that often goes unrecognised in patients with anti-Neutrophil Cytoplasmic Antibody (ANCA) associated vasculitis (AAV). We conducted a retrospective review of AAV patients on AZA maintenance therapy (N = 35). Participants were categorised into those who had experienced AZA-DHR (N = 15) and those who were AZA-tolerant (N = 20). Human leukocyte antigen (HLA) typing was performed in both groups. The primary endpoint was identification of a HLA gene association with AZA-DHR in the context of AAV. HLA-C*06:02, was solely expressed in AZA-DHR patients (33.3 %), whilst no patient who tolerated AZA carried this allele (0.0 %). This yielded a positive predictive value of 100 % for HLA-C*06:02 in predicting AZA-DHR in AAV patients, negative predictive value of 66.7 %, sensitivity of 33.3 % and specificity of 100 %. HLA-C*06:02 may predict the development of AZA-DHR in patients with AAV and inform safer therapeutic choice.

Eosinophilic granulomatosis with polyangiitis: diagnosis and treatment-related issues

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic necrotizing vasculitis of small to medium-sized vessels associated with antineutrophil cytoplasmic antibodies (ANCA). EGPA is usually diagnosed in patients with bronchial asthma (BA) and is characterized by a predominant lesion of the lungs, skin, and peripheral nervous system. ANCAs to myeloperoxidase are detected in 1/3 of patients with EGPA. Presence or absence of ANCAs differentiates 2 disease phenotypes with different clinical characteristics and prognosis. New opportunities for the treatment of EGPA appeared after identification of the key role of eosinophils in EGPA and development of targeted drugs for the treatment of eosinophilic BA that are being studied now. Aim of the review is to highlight modern approaches to the diagnosis and treatment of patients with EGPA, primarily through the use of targeted biological therapy. Conclusion. EGPA is a multisystem disease with ambivalent manifestations associated with eosinophilic or ANCA-mediated small vessel injuries. Currently, there is no “gold standard” for the diagnosis of EGPA, although the efficacy of pharmacological therapy is directly related to early detection and timely initiation of treatment. Monoclonal antibodies targeting interleukin-5 (IL-5) are an effective alternative to conventional systemic corticosteroids used alone or in combination with immunosuppressants (cyclophosphamide for induction and azathioprine for maintenance therapy) in patients with severe/refractory disease and unfavorable prognosis. The clinical benefits of the targeted anti-IL-5 drug mepolizumab were confirmed in a randomized controlled trial, and this drug was approved for the treatment of patients with EGPA. Currently, new drugs, including targeted ones, are being tested for induction and maintenance therapy. Pulmonologists and rheumatologists should coordinate patient management to improve the results of treatment and the prognosis of the disease.

Clinical case of concomitant tuberculosis and COVID-19 on the background of Churg-Strauss syndrome

BACKGROUND. Tuberculosis (especially chemoresistant), coronavirus disease (COVID-19) and Churg-Strauss syndrome (CSS), both separately are serious illnesses, and in combination with each other (tuberculosis + COVID-19, COVID-19 + CSS). The analysis of the literature also indicates the difficulty of differential diagnosis between these diseases, as they have common clinical and radiological features. The outcome of treatment depends on timely and early diagnosis of each of these diseases with the prescription of corresponding therapy. We haven’t found in the available literature described cases of concomitant tuberculosis, COVID-19 and CSS, which may be interesting in terms of diagnostic vigilance of physicians of different specialties.
 OBJECTIVE. To demonstrate the features of the simultaneous course of tuberculosis and COVID-19 in a patient with CSS on the example of a clinical case of self-observation.
 RESULTS AND DISCUSSION. During the last 19 years of her life, the patient suffered from CSS. From the treatment she received only polcortolon, which was insufficient for such a serious disease. Whereas, according to the literature, for the treatment of eosinophilic granulomatous vasculitis not only glucocorticoids should be prescribed, but also immunosuppressants (cyclophosphamide for induction and azathioprine for maintenance therapy), mepolizumab and others. During these years, the patient developed lesions of the cardiovascular system (metabolic cardiomyopathy of ethanol and eosinophilic-granulomatous-vascular origin, myocardial fibrosis with arrhythmia, heart failure of 1st degree), gastrointestinal tract (chronic gastroduodenitis, peptic ulcer of the duodenum, gallstone disease, chronic calculous cholecystitis, chronic pancreatitis), urogenital system (chronic pyelonephritis), skin (autoimmune dermatitis, hemosiderosis), respiratory system (respiratory insufficiency of the 2nd degree, chronic allergic rhinosinusitis). COVID-19 and multidrug-resistant tuberculosis joined on the background of the depleted organism. COVID-19 treatment was effective. However, the treatment of multidrugresistant tuberculosis, which the patient received for 3 months, did not have a positive effect (negative radiological dynamics on the background of continued bacterial excretion). Renal dysfunction (creatinine >140 μmol/l) and peripheral eosinophilia also persisted during this period. According to the FFS lethal risk scale, the patient had two factors, which indicated a very severe flow of the disease and a high risk of death. Acute heart failure was the reason of death.
 CONCLUSIONS. CSS (eosinophilic granulomatous vasculitis) is a rare disease that requires timely, quality and proper treatment that will prevent the development of damage of various organs and body systems (especially cardiovascular and respiratory). The presented case demonstrates a very severe course of CSS with damage of many organs and body systems in the absence of proper treatment, which could lead to timely regression of vasculitis symptoms and improve the patient’s prognosis. On the background of this syndrome, COVID-19 and multidrug-resistant tuberculosis joined. However, death has occurred as a result of acute heart failure after 3 months, that was inevitable.

Comparative efficacy and safety of rituximab, mycophenolate, methotrexate, and cyclophosphamide versus azathioprine as maintenance therapy in antineutrophil cytoplasmic antibody-associated vasculitis: A Bayesian network meta-analysis of randomized controlled trials.

In this study we aimed to compare the effectiveness and safety of rituximab, mycophenolate mofetil (MMF), methotrexate (MTX), and cyclophosphamide (CYC) with azathioprine (AZA) for maintenance treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We searched MEDLINE, EMBASE, and Cochrane databases to retrieve randomized controlled trials (RCTs) examining the efficacy and safety of rituximab, MMF, MTX, CYC, and AZA for maintenance therapy in AAV patients. We applied a random-effects, meta-analytic model in all calculations. We performed a Bayesian fixed-effects network meta-analysis to combine direct and indirect evidence from RCTs. The primary effectiveness outcome was the number of patients who experienced relapse during the maintenance phase, while the primary safety outcome was the number of serious infections. Five RCTs including 667 patients were included. Rituximab demonstrated lower relapse rates than MMF (odds ratio (OR), 0.16; credible interval (CrI), 0.07-0.38). Surface under the cumulative ranking curve (SUCRA)-based likelihood rating revealed that rituximab had the probability of being the best relapse-lowering therapy, followed by CYC, MTX, AZA, and MMF. In SUCRA-based likelihood rating, rituximab showed the greatest probability of being the best major relapse-based therapy, followed by CYC, AZA, and MMF. MMF showed a lower risk of serious infection than MTX did (OR, 0.04, 95% CrI, 0.00-0.53). SUCRA-based rating probability revealed MMF was likely the safest treatment with the lowest incidence of serious infection, followed by CYC, AZA, rituximab, and MTX, although the difference was only significant between MMF and MTX. Rituximab may be an effective relapse-lowering, maintenance treatment for patients with AAV, and MMF showed the lowest rate of serious infections among the drugs investigated.

Cost-Effectiveness of Rituximab (Fixed Schedule vs Tailored Dose) Compared With Azathioprine Maintenance Therapy in Adults With Generalized Antineutrophil Cytoplasm Antibody-Associated Vasculitis in Colombia

ObjectivesAzathioprine has been the therapy of choice for the maintenance of remission in patients with antineutrophil cytoplasm antibody (ANCA)-associated systemic vasculitis, but recent studies show that rituximab could be more effective. To evaluate the cost-effectiveness of azathioprine, fixed-schedule rituximab, and tailored-dose rituximab for ANCA-associated systemic vasculitis. MethodsA Markov model from the perspective of the Colombian healthcare system was designed with annual cycles and a 5-year time horizon, charting the following states: remission, minor relapse, major relapse, and death. The discount rate was 5%. Transition probabilities were obtained from a systematic literature review. The costs (1 US dollar = 2956 Colombian pesos in 2018) were estimated based on national drug registries and official fee manuals for procedures, along with other resources. The main outcomes were quality-adjusted life-years (QALYs) taken from the Tufts registry. Univariate and multivariate sensitivity analyses were performed. ResultsFinal costs were $1446 for azathioprine, $4898 for tailored-dose rituximab, and $6311 for fixed-schedule rituximab. QALYs gained were 3.18, 4.08, and 3.98, respectively. Rituximab was cost-effective (cost per incremental QALY gained: $4919, and $6865), and tailored-dose administration had a lower cost. Sensitivity analyses did not affect the results. ConclusionsTailored-dose rituximab was the most cost-effective treatment for ANCA-associated vasculitis. Azathioprine presented worse effectiveness and lower cost, and fixed-schedule rituximab was dominated by tailored-dose rituximab.

Treatment for Severe Lupus Nephritis: A Cost-Effectiveness Analysis in China.

Background: Lupus nephritis (LN) is the most common secondary glomerular diseases that will cause end-stage renal disease (ESRD) and renal-related death. The cost-effectiveness of various treatments for LN recommended by official guidelines has not been investigated in China. Our study is to evaluate clinical prognosis and cost-effectiveness of the current treatments for severe LN.Methods: A Markov model was simulated for 1,000 LN patients of 30 years old, over a 3-years and 30-years lifetime horizon respectively. We assessed the cost-effectiveness of six therapeutic strategies from a societal perspective, with cyclophosphamide (CYC) or mycophenolate mofetil (MMF) induction therapy followed by CYC, MMF or azathioprine (AZA) maintenance therapy. Main outcomes included quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER) and clinical prognosis. One and three times gross domestic product (GDP) per capita were used as the willingness-to-pay (WTP) thresholds. We also carried out sensitivity analysis under a lifetime horizon.Results: Compared with the baseline strategy of CYC induction and maintenance, for a 3-years horizon the most cost-effective strategy was CYC induction and AZA maintenance with $448 per QALY gained, followed by MMF induction and AZA maintenance which however was not cost-effective under the one times GDP per capita WTP threshold. For a lifetime horizon, CYC induction and AZA maintenance remained the most cost-effective strategy but MMF induction and maintenance became cost-effective under the one times GDP per capita WTP threshold and achieved a higher complete remission rate (57.2 versus 48.9%) and lower risks of ESRD (3.3 versus 5.8%) and all-cause mortality (36.0 versus 40.8%). The risk of developing ESRD during maintenance was the most influential parameter affecting ICER.Conclusions: The strategy of CYC induction followed by AZA maintenance was the most cost-effective strategy in China for short-term treatment, while the strategy of MMF in both induction and maintenance became cost-effective and yielded more desirable clinical outcomes for lifetime treatment. The uncertainty analysis supported the need for monitoring the progression to ESRD.

Efficacy of tacrolimus as maintenance therapy after cyclophosphamide for treating antineutrophil cytoplasmic antibody-associated vasculitis.

Azathioprine (AZA), methotrexate, or rituximab is used for the maintenance therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Although the efficacy of tacrolimus (TAC) in various autoimmune diseases has been demonstrated, there have been few reports on the efficacy of TAC in AAV. We investigated the efficacy of TAC as maintenance therapy for AAV and compared its efficacy with that of AZA.We retrospectively analyzed the medical records of 81 patients with AAV who received cyclophosphamide as induction therapy and AZA or TAC as maintenance therapy. All-cause death, relapse, and progression to end-stage renal disease (ESRD) were analyzed.Among 81 patients with AAV, 69 patients received AZA alone, 6 patients received TAC alone, and 6 patients received TAC after AZA for maintenance therapy. Overall, 11 patients (13.6%) died, 30 patients (37.0%) experienced relapse, and 16 patients (19.8%) progressed to ESRD during a median of 33.8 months. No significant differences were observed in cumulative patients’, relapse-free, and ESRD-free survival rates between patients administered AZA alone and TAC alone. There were no significant differences in the cumulative patients’ and relapse-free survival rate between patients who received AZA alone and TAC after AZA. However, the cumulative ESRD-free survival rate was lower in patients who received TAC after AZA than in those who received AZA alone (P = .027).Patients who received TAC as maintenance therapy showed a higher incidence of ESRD than those who received AZA; however, this might be attributed to the lack of efficacy of AZA rather than the low ESRD prevention effect of TAC.

Clinical Practice Audit on the Management of Antineutrophil Cytoplasmic Antibody–Associated Vasculitis in the Netherlands

IntroductionManaging complex and rare systemic autoimmune diseases such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) can be challenging and is often accompanied by undesirable variations in clinical practice. Adequate understanding of clinical practice can help identify essential issues to improve the care for AAV patients. Therefore, we studied the real-life management and outcomes of AAV patients in the Netherlands.MethodsIn this cohort study, we investigated clinical practice in university and nonuniversity teaching hospitals with respect to patients with a clinical diagnosis of AAV. We retrospectively collected clinical data encompassing clinical variables, medication details, and outcome parameters.ResultsData of 230 AAV patients were collected in 9 Dutch hospitals. Of these, 167 patients (73%) were diagnosed with granulomatosis with polyangiitis, 54 (24%) with microscopic polyangiitis and 9 (4%) with eosinophilic granulomatosis with polyangiitis. One hundred sixty-six patients (72%) had generalized disease. The median year of diagnosis was 2013 (range 1987–2018). Besides steroids, oral cyclophosphamide was the most used drug (50%) for induction therapy and azathioprine (68%) for maintenance therapy. Adverse outcomes were major infections in 35%, major relapses in 23%, malignancy in 10%, major cardiovascular events in 8%, and end-stage renal disease in 7%.ConclusionOral cyclophosphamide was the most frequently used induction therapy, azathioprine for maintenance therapy; over time, the use of rituximab is increasingly employed. Major infection and relapses are the most prevalent adverse outcomes. This audit resulted in important indicators for treatment of AAV patients that can be implemented for future, national audits to improve the outcomes of AAV patients.

Comparison of relapse rates in Behçet’s disease with venous involvement on different doses of azathioprine therapy, a retrospective observational study

The aim of this study was to investigate relapse rates in azathioprine (AZA) maintenance therapy at different doses in Behçet's disease (BD) with venous involvement. Clinical records of patients who met the diagnostic criteria of International Study Group (ISG) for BD, were diagnosed with venous involvement of BD for at least 6months and sustained clinical remission with AZA for at least 3months were analyzed retrospectively. The analysis cohort was divided into 2 groups based on AZA dose (Group A: ≥ 2mg/kg/d and Group B: <2mg/kg/d). Relapse was defined as requiring another antirheumatic/immunosuppressive drug or more than dose of 10mg/d of prednisolone. Of 78 patients who were included into the study, there was no significant difference between the 2 groups in terms of age, gender and clinical characteristics. Mean relapse-free survival time was found to be higher in group A compared to group B (111.6±11.2, 95% CI 89.5±133.8 versus 51.5±6.1, 95% CI 39.5±63.4 months). Relapse-free survival rate was less in the group receiving low-dose AZA and shows the importance of effective dose of AZA in maintenance therapy.

Granulomatosis With Polyangiitis and Microscopic Polyangiitis: A Systematic Review and Meta-Analysis of Benefits and Harms of Common Treatments.

ObjectiveThe aim of this systemic review is to compare different treatments for patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) to inform evidence‐based recommendations for the American College of Rheumatology (ACR)/Vasculitis Foundation (VF) Vasculitis Management Guidelines.MethodsA systemic review was conducted by searching articles in English using OVID Medline, PubMed, Embase, and the Cochrane Library. Articles were screened for suitability in addressing PICO questions, with studies presenting the highest level of evidence given preference.ResultsA total of 729 full‐text articles addressing GPA and MPA PICO questions were reviewed. For remission induction, rituximab was shown to be noninferior to cyclophosphamide (CYC) (odds ratio [OR]: 1.55, moderate certainty of evidence). The addition of plasma exchange to induction therapy in severe disease did not improve the composite end point of death or end stage renal disease (hazard ratio [HR]: 0.86 [95% confidence interval CI: 0.65, 1.13], moderate certainty of evidence). In nonsevere disease, methotrexate was noninferior to CYC for induction of remission (remission at 6 months of 90% vs. 94%). For maintenance of remission, methotrexate and azathioprine showed no difference in the risk of relapse over a mean follow‐up of 29 months (HR: 0.92, [95% CI: 0.52, 1.65]low certainty of evidence). As maintenance therapy, rituximab was superior to a tapering azathioprine strategy in major relapse‐free survival at 28 months (HR: 6.61, [95% CI: 1.56, 27.96], moderate certainty of evidence). In two randomized trials, longer‐term azathioprine maintenance therapy (>24 months) is associated with fewer relapses without an increase in adverse events.ConclusionThis comprehensive systematic review synthesizes and evaluates the benefits and toxicities of different treatment options for GPA and MPA.

Multicentric study comparing cyclosporine, mycophenolate mofetil and azathioprine in the maintenance therapy of lupus nephritis: 8years follow up.

The ideal long-term maintenance therapy of Lupus Nephritis (LN) is still a matter of debate. The present study was aimed at comparing the efficacy/safety profile of cyclosporine (CsA), mycophenolate mofetil (MMF) and azathioprine (AZA) in long-term maintenance therapy of LN. We performed a retrospective study of patients with biopsy-proven active LN. After induction therapy, all patients received maintenance therapy with CsA, MMF or AZA based on medical decision. Primary endpoint was complete renal remission (CRR) after 8years (defined as proteinuria < 0.5g/24h, eGFR > 60ml/min/1.73mq); secondary endpoints were: CRR after 1year, renal and extrarenal flares, progression of chronic kidney disease (CKD stage 3 or above) and side-effects. Out of 106 patients, 34 received CsA, 36 MMF and 36 AZA. Clinical and histological characteristics at start of induction therapy were comparable among groups. At start of maintenance therapy, CsA patients had significantly higher proteinuria (P = 0.004) or nephrotic syndrome (P = 0.024) and significantly lower CRR (23.5% vs 55.5% on MMF and 41.7% on AZA, P = 0.024). At one year, CRR was similar in the three groups (79.4% on CsA, 63.8% on MMF, 58.3% on AZA, P = 0.2). At 8years, the primary endpoint was achieved by 79.4% of CsA vs 83.3% of MMF and 77.8% of AZA patients (P = 0.83); 24h proteinuria, serum creatinine, eGFR were similar. CKD stage 3 or above developed in 8.8% of CsA, in 8.3% of MMF and in 8.3% of AZA patients (P = 0.92). Flares-free survival curves and incidence of side-effects were not different. This is the first study comparing CsA, MMF and AZA on long-term LN maintenance therapy. All treatments had similar efficacy in achieving and maintaining CRR, despite more severe baseline clinical features in patients treated with CsA.

Patients' Educational Program Could Improve Azathioprine Adherence in Crohn's Disease Maintenance Therapy.

Aim To determine the risk factors of nonadherence to azathioprine (AZA) maintenance therapy for Crohn's disease (CD) and to evaluate the influence of patients' educational program on adherence to AZA maintenance therapy. Methods Patients receiving AZA as maintenance therapy for CD were enrolled. Demographic data, clinical data, and usage information were collected. Univariate and multivariate analyses were performed to identify the risk factors of nonadherence. Then, patients' educational program was conducted. One year after the program, the improvements in adherence and relapse rates were compared between educational and noneducational groups. Results A total of 378 CD patients receiving AZA as maintenance therapy were enrolled from September 2008 to September 2018. Nonadherence occurred in 43.9% (166/378) of patients. Univariate analysis revealed that young age, education, alcoholism, anxiety, depression, concern belief, and lack of necessity belief and AZA knowledge were risk factors of nonadherence (P < 0.05). Multivariate logistic regression showed that anxiety (OR 6.244, 95% CI 2.563–15.213), depression (OR 3.801, 95% CI 1.281–11.278), and concern belief (OR 19.531, 95% CI 3.393–120.732) were independent risk factors of nonadherence. Necessity belief (OR 0.961, 95% CI 0.925–0.999) and AZA knowledge (OR 0.823, 95% CI 0.758–0.903) were protective factors of adherence. One year after the AZA educational program, the necessity belief, AZA knowledge, and adherence of the educational group significantly improved (P < 0.05). Concern belief was significantly lower in the educational group than that in the noneducational group (P < 0.05). Moreover, the noneducational group suffered significantly higher endoscopic relapse rates than that the educational group (15.9% vs. 30.1%, P = 0.035). Conclusions Nonadherence occurred frequently in CD patients receiving AZA maintenance therapy. Educational programs could improve patients' adherence mainly by promoting their beliefs and knowledge of AZA and could reduce relapse rates during treatment.

EP45 What’s the chance of precipitation?

Abstract Background This project was undertaken to review patients testing positive for cryoglobulins. We wanted to establish the numbers of patients with different types of cryoglobulins, to determine whether there were any shared characteristics and whether there was any consensus on management. Methods Retrospective review of records of Sheffield Teaching Hospital patients testing positive for cryoglobulins January 2014-December 2018. Results 374 cryoglobulin tests were requested. 43 were positive (in 33 patients).There were 9 Type I cryoglobulins, including IgG and IgM lambda and kappa. Titres ranged from 0.07-47.5g/L. All patients had an underlying haematological condition. 2 patients had rash and 1 acute kidney injury (AKI), but there were no other clinical features of cryoglobulinaemia. 1 patient received treatment for cryoglobulinaemia secondary to MGUS with prednisolone, plasma exchange and Velcade/Thalidomide/Dexamethasone. Otherwise the cryoglobulins appear to be a laboratory finding with minimal clinical significance.There were 17 Type II cryoglobulins in 12 patients. The most common pattern was IgM kappa monoclone with polyclonal immunoglobulin (71%). Titres ranged from 0.03-5.4g/L. Patients’ underlying conditions were malignant, infective and inflammatory. 7 patients had rash, 2 arthralgia/arthritis, 4 Raynaud’s, 3 paraesthesia and 2 AKI. The presence of cryoglobulins was not considered significant in 5 patients (titres 0.03-0.39g/L). 3 patients were treated for underlying malignancy or infection and cryoglobulins monitored. 2 patients (titres 0.16 and 1.97g/L) were treated for renal disease in the presence of cryoglobulins with prednisolone and Rituximab in 1 case and prednisolone, Cyclophosphamide and plasma exchange in the other. 2 patients were diagnosed with cryoglobulinaemic vasculitis (titres 0.5g/L and 0.03g/L). 1 was treated with prednisolone and Azathioprine. The other had previously been treated with prednisolone and cyclophosphamide, then azathioprine maintenance therapy; the relapse during this study period was treated with methylprednisolone, plasma exchange and Rituximab.There were 16 Type III cryoglobulins in 14 patients. By definition all had polyclonal immunoglobulins. Titres ranged from 0.06-4.64g/L. Patients’ underlying conditions were malignant, infective and inflammatory. 7 patients had rash, 4 arthralgia/arthritis, 2 paraesthesia and 1 AKI. The presence of cryoglobulins was not thought significant in 5 patients (titres 0.08 to 0.45g/L). 7 patients were treated for underlying infection or rheumatological condition and the cryoglobulins monitored. 1 patient (already reported in the Type II section) was treated for renal disease in the presence of cryoglobulins. 1 patient (titre 0.12g/L) with a diagnosis of cryoglobulinaemic vasculitis was treated with prednisolone and azathioprine, then mycophenolate. Conclusion The study confirms that cryoglobulins are rare and that clinically significant disease related to them is even rarer. Given the small numbers it is difficult to identify strong trends in presentation or treatment. However, it does show that higher cryoglobulin titres do not correlate with higher rates of disease activity in terms of cryoglobulinaemia or cryoglobulinaemic vasculitis. Disclosures: R. Smith: None. G. Wild: None. S. Carter: None.

Highly sensitive and rapid determination of azathioprine metabolites in whole blood lysate by liquid chromatography–tandem mass spectrometry

Individualized therapy involves genetic test of drug metabolism, which provides information about the initial dose and therapeutic drug monitoring for adjusting the subsequent dose. Consequently, toxic side effects are expected to be minimized and therapeutic effects to be maximized. In this study, an ultra-performance liquid chromatography tandem mass spectrometry method that was specific, accurate and sensitive was developed to simultaneously determine azathioprine two metabolites, 6-thioguanine nucleotides (6-TGN) and 6-methyl-mercaptopurine riboside (6-MMPr) in the whole blood lysate. We precipitated the sample by trifluoroacetic acid under the protection of dithiothreitol, with 6-MMPr and 6-TGN being hydrolyzed to produce 6-methymercaptopurine and 6-thioguanine. In the chromatographic separation, Waters ACQUITY BEH C18 (2.1 × 100 mm, 1.7 μm) chromatographic column was applied and gradient elution was conducted with 0.02 mol/L ammonium acetate buffer (which contains 0.3% formic acid) and acetonitrile at a flow rate of 0.4 ml/min. Tandem mass spectrometry in multiple reaction monitoring mode was applied for detection via electrospray ionization source in positive ionization mode. The analyzing process lasted for no more than 2 min. The calibration curve for each metabolite fitted a least squares model (weighed 1/X) from 1.25 to 5000 ng/ml (r2 > 0.99). The ion pairs were detected as 6-MMP m/z 167.07 → 152.15, 6-TG m/z 168.06 → 134.13, and internal standard m/z 171.07 → 137.14. Under the guidance of FDA guidelines for bioanalytical method validation, we carried out validation and obtained satisfactory results. The method was successfully utilized for monitoring the concentrations of each metabolite from 65 affected patients who had received azathioprine maintenance therapy and achieved optimal results.

SUN-405 From Diabetes Insipidus to Primary Polydipsia: The Dynamic State of Water Balance in Neurosarcoidosis

Background: Central diabetes insipidus (DI) may be transient and resolve days after pituitary surgery.Here we present the case of a patient with neurosarcoidosis who experienced resolution of his DI over a year after confirmatory testing, and unexpectedly developed primary polydipsia. Clinical case: A 32 year old male was diagnosed with panhypopituitarism and neurosarcoidosis 14 months prior to admission when he presented with hypotension and acute encephalopathy. After receiving steroid and thyroid replacement, he improved but he developed polyuria, and had persisting hypernatremia and dilute urine. Patient underwent a water deprivation test which confirmed DI (had 100% increase in Uosm and had Uosm of >300 mosm/kg after desmopressin). He was discharged on Desmopressin 0.05mg daily, levothyroxine, hydrocortisone, and treatment for his neurosarcoidosis. Patient was again found nonresponsive and hypotensive, leading to most recent hospital readmission. He had a 1 week history of progressive weakness and lethargy and had been unable to take his medications for a few days prior to admission.The patient had completed 48 weeks of immunosuppressive therapy for his neurosarocidosis with prednisone (completed taper) and azathioprine (maintenance therapy) prior to admission. Lab testing showed a plasma sodium of 132mmol/L and a Uosm of 263mosm/kg. Patient was prescribed high dose IV hydrocortisone and levothyroxine. Desmopressin was held. MRI brain revealed leptomeningeal enhancement consistent with known neurosarcoidosis and steroids were switched to high dose prednisone. A week later, when patient’s mentation began to improve, he complained of increased thirst and polyuria (4.5L/day). His plasma sodium remained between 131-134mmol/L and urine was found to be consistently dilute (s.g.1.006-1.008). Team initiated IV fluids with saline and patient was drinking over 2 L of water per day. Patient’s sodium (off Desmopressin) reached a nadir of 128mmol/L and urine output increased to 5 L per day. Patient’s IV fluids were stopped and he was placed on water restriction (1.5L/day). Patient was discharged 10 days after stopping desmopressin, with improved mentation, a reduction in urine output (1.8 L/day); his plasma sodium ranged between 128 -130mmol/L and urine specific gravity of 1.008 confirming resolution of his DI and suggesting the development of primary polydipsia. Conclusion: Physicians should recognize the dynamic nature of water balance regulation in patients with panhypopituitarism due to neurosarcoidosis. Continuation of desmopressin without periodic evaluation of fluid and electrolyte balance may lead to the development of iatrogenic hyponatremia, particularly when DI resolves and dysregulation of patient’s thirst mechanism is present. Reference: Hypothalamo-pituitary sarcoidosis: a multicenter study of 24 patients QJM,Volume 105, Pages 981-995 C. Langrand et al.

Azathioprine Hypersensitivity Syndrome in a Cohort of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Patients

Azathioprine hypersensitivity syndrome is a rare complication of azathioprine therapy. Its symptoms resemble infection or relapse of inflammatory disease, hindering correct diagnosis. Current literature is limited to sporadic case reports and reviews. To estimate the incidence of azathioprine hypersensitivity syndrome and describe its characteristics in the context of an observational cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Also, to facilitate early recognition and awareness among clinicians. Within a cohort of 290 patients with ANCA-associated vasculitis receiving azathioprine maintenance therapy, frequency of azathioprine hypersensitivity was described and characteristics were compared between hypersensitive and nonhypersensitive patients. Clinical picture, laboratory abnormalities, and concurrent medication of patients with azathioprine hypersensitivity were described. Of 290 patients, 25 (9%) experienced azathioprine hypersensitivity after a median of 14 (interquartile range [IQR] 12-18) days. Frequent symptoms were fever (100%), malaise (60%), arthralgia (36%), and rash (32%). All patients used prednisolone (median 10 mg/day, IQR 9.4-16.3 mg/day) at the time of the hypersensitivity reaction. Most patients had a rise in C-reactive protein (CRP), leukocyte counts, and neutrophil counts, but no eosinophilia. Thiopurine S-methyltransferase (TPMT) activity was significantly lower in hypersensitive patients (median 74.4 [IQR 58.0-80.1] nmol/gHb/L) compared with controls (median 81.4 [71.9-90.5] nmol/gHb/L), P= .01. Hypersensitive patients had a higher risk of relapse (hazard ratio 2.2, 95% confidence interval 1.2-4.2; P= .01). Azathioprine hypersensitivity syndrome is strikingly common in ANCA-associated vasculitis, might be associated with reduced TPMT activity, is accompanied by an increase in neutrophil counts, and may occur even during concomitant prednisolone therapy. Proper recognition may prevent unnecessary hospital procedures and damage to the patient.

Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss).

Eosinophilic granulomatosis with polyangiitis (EGPA), formerly called Churg-Strauss syndrome, is a systemic necrotizing vasculitis of small- and medium-size vessels, characterized by asthma and blood eosinophilia. EGPA typically occurs in patients with preexisting asthma, and involves the skin, lungs, and peripheral nerves. Poor-prognosis factors (i.e., involvement(s) of the gastrointestinal tract, heart, and/or kidney) have been assessed with the Five-Factor Score (FFS). One-third of the patients have anti-myeloperoxidase antineutrophil cytoplasm antibodies, and their presence seems to differentiate between two phenotypes, with different clinical characteristics and prognoses. Overall survival has improved markedly since the use of glucocorticoids and immunosuppressants, but relapse rates remain high. All patients require glucocorticoids, and for those with severe/refractory disease and FFS-defined poor prognoses, immunosuppressants should be used (cyclophosphamide for induction and azathioprine for maintenance therapy). Recent advances in EGPA management, including several novel immunomodulatory drugs and targeted biotherapies, were or are being evaluated to improve EGPA patients' prognoses.

Rituximab induction therapy for de novo ANCA associated vasculitis in pregnancy: a case report

BackgroundThe diagnosis of antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is rare in pregnancy but potentially life threatening. There are no randomized controlled trials to guide the management of AAV in pregnancy and fetal safety data remains limited. Rituximab administration, a treatment for AAV, has been reported in pregnant women with reassuring fetal outcomes in the oncology and rheumatology literature; however, no published reports describe its use in AAV.Case presentationWe present a case of de novo myeloperoxidase positive (MPO) AAV diagnosed at 22 weeks gestation. Clinical presentation included elevated serum creatinine at 177 μmol/L, hematuria and nephrotic range proteinuria along with high-titre MPO. Diagnosis was confirmed by renal biopsy. Patient was treated with methylprednisolone IV followed by oral prednisone 70 mg daily and Rituximab 650 mg IV weekly for four weeks followed by azathioprine maintenance therapy and prednisone taper. Delivery occurred at 29 weeks gestation via cesarean section for maternal neurologic symptoms concerning for preeclampsia. Maternal and fetal CD + 19 cells were depleted at time of delivery with associated fetal lymphopenia in the absence of infection or other complications related to Rituximab use. The patient experienced a reduction in proteinuria and inflammatory markers following Rituximab therapy; however, serum creatinine increased to 375 μmol/L by 11 weeks post-partum.ConclusionWe report the first use, to our knowledge, of Rituximab with corticosteroids for induction therapy of AAV in pregnancy.

Longterm Outcomes of 188 Japanese Patients with Eosinophilic Granulomatosis with Polyangiitis.

Patients with eosinophilic granulomatosis with polyangiitis (EGPA) frequently experience relapses, which lead to cumulative organ damage. In this retrospective observational study, we aimed to reveal the risk factors for relapse in EGPA. A total of 188 Japanese patients with EGPA diagnosed between 1996 and 2015 were identified from medical records in 10 hospitals. The diagnosis was based on the American College of Rheumatology 1990 criteria or Lanham's criteria. Baseline characteristics, treatments, asthma exacerbation, and relapses were evaluated by retrospective chart review. The median followup period was 56 months. The median age at disease onset was 59.7 years. At the disease onset, 95.2% of the patients had a history of bronchial asthma and 44.7% were positive for antineutrophil cytoplasmic antibodies. The cumulative survival and relapse-free survival rates at 5 years were 89.6% and 64.0%, respectively. Multivariate analysis with 2 models, proportional hazards, and competing risk models, was performed to identify the factors associated with relapse. The proportional hazards model identified azathioprine (AZA) maintenance therapy and high eosinophil counts at onset as independent factors with lower relapse risks, and high immunoglobulin E (IgE) levels at onset as a risk factor for relapse. The competing risk model identified no statistically significant factors. Although potential benefit of AZA maintenance therapy in preventing relapse of EGPA was suggested by the proportional hazards model, there was a discrepancy in the results between the models. Eosinophil counts and IgE levels at onset were also identified as candidates of factors associated with relapse in EGPA.