Intravenous Cyclophosphamide Therapy Research Articles

Intravenous cyclophosphamide therapy for patients with severe ocular inflammatory diseases who failed other immunomodulatory therapies

BackgroundOcular inflammatory diseases, including scleritis and uveitis, have been widely treated with immunomodulatory therapies (IMTs) as a steroid-sparing approach. Such strategy includes conventional therapies (antimetabolites, alkylating agents, and calcineurin inhibitors) as well as biologic agents like adalimumab, infliximab, rituximab, and tocilizumab. Cyclophosphamide (CP) is an alkylating agent and mainly inhibits the functioning of both T and B cells. Though known to have potential adverse events, including bone marrow suppression, hemorrhagic cystitis, and sterility, CP has been shown to be efficacious, especially in recalcitrant cases and when used intravenous (IV) for a limited period.Main findingsWe conducted a retrospective case-series to assess the safety and efficacy of CP therapy for patients with severe ocular inflammatory diseases who failed other IMTs. Medical records of 1295 patients who presented to the Uveitis Clinic at the Byers Eye Institute at Stanford between 2017 and 2022 were reviewed. Seven patients (10 eyes) who received CP therapy for ocular inflammatory diseases with at least one year of follow-up were included. The mean age of the patients (4 males, 3 females) was 61.6 ± 14.9 (43.0–89.0) years. Clinical diagnoses included necrotizing scleritis (5 eyes), peripheral ulcerative keratitis (2 eyes), orbital pseudotumor (1 eye), HLA-B27 associated panuveitis and retinal vasculitis (2 eyes). Ocular disease was idiopathic in 3 patients, and was associated with rheumatoid arthritis, IgG-4 sclerosing disease, dermatomyositis, and ankylosing spondylitis in 1 patient each. All the patients had history of previous IMT use including methotrexate (5), mycophenolate mofetil (3), azathioprine (1), tacrolimus (1), adalimumab (2), infliximab (4), and rituximab (1). The mean follow-up time was 34.4 ± 11.0 (13–45) months, and mean duration of CP therapy was 11.9 ± 8.8 (5–28) months. Remission was achieved in 5 patients (71.4%). Four patients (57.1%) experienced transient leukopenia (white blood cell count < 4000/mL).Short conclusionCP therapy can be considered a potentially effective and relatively safe therapeutic option for patients with severe ocular inflammatory diseases who failed other IMTs including biologics (TNFa and CD20 inhibitors).

Intravenous cyclophosphamide therapy in children with calcineurin inhibitor-resistant steroid-resistant nephrotic syndrome in a resource-limited setting.

In pediatric steroid-resistant nephrotic syndrome (SRNS), calcineurin inhibitors (CNIs) are recommended as first-line therapy, with efficacy ranging between 60 and 80%, implying a substantial proportion will exhibit CNI resistance. Which alternate immunosuppressive therapy should be used in non-genetic pediatric SRNS exhibiting CNI resistance is especially relevant in low- to middle-income countries (LMIC), where the prohibitive costs of certain drugs such as monoclonal antibodies often determine therapy choice. The primary objective was to assess the efficacy of intravenous cyclophosphamide in a proportion of children aged 1-18years with CNI-resistant SRNS with a complete response (CR) or partial response (PR) at 6months from commencement of pulse therapy. The secondary objectives were to assess the proportion and profile of infections and adverse effects. Of 90 children with idiopathic SRNS presenting between January 2013 and December 2022, 29 (32.2%) had CNI resistance and were enrolled. They were administered monthly intravenous cyclophosphamide pulses (6 pulses). Median (IQR) duration of follow-up was 48 (29.5, 63.5) months. At the end of 6months of cyclophosphamide therapy, 13 (44.8%) attained CR and 4 (13.8%) attained PR, with an overall cyclophosphamide success rate of 58.6%. The efficacy of intravenous cyclophosphamide was higher in secondary (9/10; 90%) versus primary CNI resistance (8/19; 42.1%) (p = 0.029). Three children (3/29; 10.3%) developed systemic infections within 12months of initiation of cyclophosphamide therapy, similar to the rate of systemic infections among children receiving CNI for SRNS management (6/41; 14.6%) (p = 0.85). It is prudent to try intravenous cyclophosphamide in CNI-resistant SRNS in LMIC, given the reasonable cost and good efficacy rates (58.6%).

Intravenous Cyclophosphamide Therapy for Anti-IFN-γ Autoantibody-Associated Talaromyces marneffei Infection.

High titers of anti-interferon-γ autoantibodies (AIGAs) are an important factor leading to persistent, relapsed, and refractory infections in HIV-negative hosts infected with Talaromyces marneffei (TM). We report 5 patients treated with pulses of high-dose intravenous cyclophosphamide (IVCY) who were followed for 2 years. Before IVCY therapy, all patients had multiple relapses, with a median (interquartile range [IQR]) of 2 (1-3) instances of relapse. The median serum AIGA titers (IQR) were 58 753 (41 203-89 605) ng/mL at diagnosis, 48 189.4 (15 537-83 375) ng/mL before IVCY therapy, and 10 721.2 (5637-13 245) ng/mL at the end of IVCY therapy (P < .05). After 3 months of follow-up, the median AIGA titers (IQR) rose gradually to 21 232.6 (9896-45 626) ng/mL, and to 37 464.2 (19 872-58 321) ng/mL at 24 months (P < .05). Five patients discontinued antimicrobial therapy within 3-12 months after completion of IVCY therapy, but only 1 patient had a relapse. In conclusion, pulses of short-term and high-dose IVCY can effectively reduce AIGA titers.

Efficacy and Short Term Outcome of Intravenous Cyclophosphamide Therapy in Children with Lupus Nephritis

Background: Renal involvement is one of the most common and severe manifestations of paediatric systemic lupus erythematosus patients. Intravenous pulse cyclophosphamide (CYC) therapy is effective for lupus nephritis patients observed in different studies. Objective: To evaluate the efficacy and short term outcome of intravenous CYC therapy in renal involvement among paediatric SLE cases. Materials and Methods: This retrospective study was conducted at the department of Paediatrics, Bangabandhu Sheikh Mujib Medical University from January 2018 to December 2021. Sixty-two pSLE patients with renal involvement who met ACR revised classification criteria and completed their follow-up were enrolled in the study. All patients received intravenous CYC monthly for six months along with initially intravenous pulse methylprednisolone followed by oral prednisolone. During the study period, patients were monitored clinically and laboratory evaluations were done at baseline, 3rd and after 6th months of follow-up. Results: Among the cases, the female:male ratio was 5.9:1 and mean age was found 12.42 ± 2.13 years. After 3 months of CYC therapy, most patients were clinically improved in haematuria, hypertension, oedema, SLEDAI score and biochemically by ESR, C3, C4, S, Creatinine, Anti-ds-DNA titers, 24-hour urine protein. These initial improvements were further enhanced after 6 months of therapy. Short term outcomes demonstrated that 50%, 38.7% and 11.3% of patients had complete, partial and no responses respectively at the last follow-up. Conclusion: Intravenous CYC therapy effectively treated lupus nephritis patients observed in this study. Around 88% of pSLE patients had complete and partial responses according to EULAR criteria. Hypertension, ant-ds-DNA titers, proteinuria and serum complements were identified as a predictor of remission.

P047 The triple M threat of check-point inhibitors - an emerging overlap syndrome

Abstract Background/Aims The objective of this abstract is to raise awareness on an emerging overlap syndrome of life-threatening immune-related adverse events, manifesting as a triad of myositis, myocarditis and myasthenia gravis in immune check-point inhibitor (ICI) treated patients. It highlights the success of combination, aggressive and prompt immunosuppression with high dose intravenous steroid, cyclophosphamide, rituximab and intravenous immunoglobulin therapy, in two patients presenting at Guy’s and St Thomas’s Hospital, London with this overlap syndrome following pembrolizumab therapy. Methods Case presentation. Case 1: 75-year-old Caucasian gentleman receives one dose of pembrolizumab for metastatic melanoma. Two weeks later, he presents with myalgia, weakness, elevated CK 10,000. Troponin T is raised 459, ECG shows right bundle branch block (RBBB) and on day 3, he rapidly descends into complete heart block then cardiac arrest. Return of spontaneous circulation is obtained and a permanent pacemaker (PPM) inserted. On day 6, myocardial biopsy confirms acute myocarditis. He develops progressive muscle weakness, dysphagia and Type 2 respiratory failure. He receives 3 doses of IV methylprednisolone, in addition to intravenous immunoglobulins (IVIG) and intravenous cyclophosphamide. EMG shows mild myopathic features, positive AChR antibody, SSA/Ro60 and myositis-specific SRP antibodies and he becomes dependent on non-invasive ventilation. He commences pyridostigmine for myasthenia gravis. On day 19 two doses 1g Rituximab two weeks apart is administered. Monthly IVIG continues for three months and he completes 6 cycles of 500mg cyclophosphamide. A year following discharge, he is maintained on prednisolone 5mg OD with no additional immunosuppression and significantly improved muscle strength. Case 2: 77-year-old Caucasian gentleman receives one dose of pembrolizumab for metastatic melanoma. Four weeks later, he presents with myalgia, bilateral ptosis, muscle weakness and breathlessness. Bloods show CK 6467, troponin T 1058. He promptly receives 3 doses of IV methylprednisolone in addition to IVIG. A PPM is inserted electively as ECGs show RBBB and intermittent bradyarrhythmias. His anti-Ro/SSA-52 antibody is positive and AChR and myositis-specific antibodies are negative. He trials neostigmine due to persistent ptosis. On Day 6, muscle biopsy confirms immune-mediated necrotising myositis and he commences intravenous cyclophosphamide 500mg followed by 5 further cycles. On day 7, 1g intravenous rituximab is administered and repeated two weeks later, additional to monthly IVIG for five months. 6 months later, his CK has normalised and he has no residual muscle weakness. Results n/a Conclusion Although a rare complication of ICIs, this triad of myositis, myocarditis and myasthenia gravis can be potentially severe and fatal. With ICI reshaping the prognosis of several cancers and pembrolizumab gaining recent further approvals, we will increasingly encounter this therapeutic challenge. Therefore, raising awareness of this overlap syndrome amongst rheumatologists is even more critical to allow for prompt recognition and treatment with immunosuppression. Disclosure A. Mootoo: None. A. Masood: None. P. Maghsoudlou: None. D. D'Cruz: None.

Effect of Cyclophosphamide and Glucocorticoid Therapy in IgA Nephropathy: A Single-Center Retrospective Analysis.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis in adults, which causes ESKD in ≤45% of patients in the long term. The optimal therapeutic approach remains undetermined. In this study, we report the results of a single-center retrospective analysis of patients with IgAN. We retrospectively evaluated the therapeutic approach and outcome of all patients at our center with biopsy-proven IgAN between 2000 and 2020, focusing on the effect of intravenous cyclophosphamide therapy combined with glucocorticoids ("immunosuppressive therapy group"). The control group received standard supportive care. Patients in the immunosuppressive therapy group had worse kidney function before the initiation of therapy, as indicated by higher serum creatinine, more proteinuria, and a higher degree of hematuria than the control group; they also displayed a higher body mass index. The Oxford classification of IgA nephropathy (MEST-C score) suggested more inflammatory activity in the immunosuppressive therapy group, including more crescents and endocapillary hypercellularity. During the follow-up, proteinuria and hematuria decreased in both groups, and to a significantly greater extent in the immunosuppressive therapy group. Cyclophosphamide treatment significantly improved kidney function as determined by the fold-change of eGFR during the observation period. The number of infections and hospitalizations did not differ, but the incidence of diabetes was increased in the immunosuppressive therapy group. This study suggests immunosuppressive therapy with cyclophosphamide combined with glucocorticoids improves kidney function, proteinuria, and hematuria. The therapy was safe for infectious complications, but was associated with an increased incidence of diabetes, which might be attributable in part to the use of steroids in patients with a higher body mass index at baseline. Although immunosuppressive therapy in IgAN remains controversial, our findings suggest that at least some patients benefit from more aggressive therapy.

Urotoxicity and safety data of low-dose intravenous cyclophosphamide therapy for rheumatic diseases: A Single-Center retrospective cohort study

Despite its effectiveness in rheumatic diseases, cyclophosphamide (CYC) treatment should be used with caution due to its side effects. CYC is thought to pose a risk in the development of hemorrhagic cystitis and bladder cancer. This study aims to determine the incidence of hemorrhagic cystitis and bladder cancer with intravenous low-dose CYC therapy used in the treatment of rheumatic diseases. A total of 211 adult patients with rheumatic disease treated with intravenous CYC were evaluated in this retrospective study conducted between January 2006 and May 2021. Patient data including cumulative CYC dose, treatment frequency, duration of treatment, side effects, such as hemorrhagic cystitis and bladder cancer were acquired from medical archives. The mean follow-up period was 48.5 (3–180) months, and the mean cumulative CYC dose was 5g (2–19g). None of the patients received mesna therapy concurrent with CYC therapy. 11 patients developed hemorrhagic cystitis (5.2%). Hemorrhagic cystitis was found to be statistically significantly associated with the number of CYC cycles (p=0.04). All patients were asymptomatic. No statistically significant difference was observed between hemorrhagic cystitis, treatment duration, and cumulative dose for CYC therapy in rheumatic diseases. Malignancy developed in 12 patients (5.7%) after CYC treatment. Bladder cancer was observed in 1 patient. According to our findings, the only risk factor for hemorrhagic cystitis in patients receiving CYC was the number of CYC cycles. Intravenous CYC regimen did not cause symptomatic hemorrhagic cystitis. Low-dose IV CYC may be safe in terms of serious urotoxic side effects when used at the appropriate dose, duration and frequency.

Gastrointestinal: Lupus mesenteric vasculitis of the colon diagnosed using endoscopic biopsy.

A 20-year-old woman with a 6-year history of systemic lupus erythematosus (SLE) was referred to our hospital for diarrhea and epigastric pain that had lasted for 2 months. She achieved remission through pulse-steroid and intravenous cyclophosphamide therapy at disease onset. Maintenance therapy with daily doses of 5-mg prednisolone and 1-g mycophenolate mofetil prevented recurrence of SLE symptoms. The patient initially experienced diarrhea and epigastric pain 2 months prior to presentation, then experienced a gradual worsening of symptoms. Esophagogastroduodenoscopy, abdominal ultrasound, and computed tomography taken 2 weeks before presentation showed no significant findings. Colonoscopy revealed multiple aphthae throughout the large intestine (Fig. 1a). A daily dose of 30 mg oral prednisolone was administered for 13 days, but the symptoms worsened and the patient developed a fever of over 38°C. Colonoscopy at presentation revealed multiple punched-out ulcers from the ascending to the descending colon (Fig. 1b). Forceps biopsy specimens were obtained from the lesion, and histopathological examination of biopsy specimens demonstrated neutrophil infiltration around small vessels with vessel disruption (Fig. 2). We therefore diagnosed the patient with lupus mesenteric vasculitis (LMV) and treated with intravenous cyclophosphamide therapy. The symptoms improved immediately and follow-up colonosocpy taken 4 months after presentation revealed that the colonic ulcers had healed into scars (Fig. 1c). LMV is associated with critical organ involvement in SLE patients, with prevalence ranging from 0.2% to 9.7%. LMV mainly involves the jejunum and ileum, and only 0.8% of cases have colorectal lesions. The typical endoscopic findings of colonic LMV are reported to be multiple punched-out ulcers, as in our case. Delaying immunosuppressive therapy in patients with LMV can lead to fatal outcomes. In the present case, colonosocpy could reveal minimal colonic lesions (Fig. 1a), while an abdominal computed tomography, the golden standard for the diagnosis of LMV, showed no significant findings in an early stage of LMV. Colonoscopy was able to detect rapid progression to multiple punched-out ulcers (Fig. 1b) and confirm the histological diagnosis of LMV (Fig. 2). These findings allowed us to correctly diagnose LMV and immediately perform intensive therapy.

Central Retinal Arterial and Venous Occlusion in a Patient with Systemic Sclerosis and a Review of the Related Literature

Systemic sclerosis (SSc) is known to cause serious complications at an advanced stage. However, serious ocular complications such as central retinal artery occlusion (CRAO) and/or central retinal vein occlusion (CRVO) have only been reported in a few cases to date. A 51-year-old man with severe Raynaud’s phenomenon, scleroderma up to the forearm and a negative anti-nuclear antibody (ANA) finding developed pulmonary fibrosis (PF) and was admitted to the hospital for the treatment of dyspnea under the diagnosis of SSc. A transbronchial lung biopsy performed 10 days after admission demonstrated mucoid intimal thickening (MIT) of the small arteries in the peripheral lung tissue and the bronchial wall. Prednisolone (PSL), ciclosporin and nintedanib were prescribed for PF treatment but failed to induce any apparent improvement in dyspnea. Finally, methylprednisolone pulse therapy (1.0 g, 3 times) and intravenous cyclophosphamide (IVCY, 500 mg, 6 times) therapy were instituted with a subsequent decrease in the patient’s Krebs von den Lungen 6 (KL-6) and surfactant protein D (SP-D) levels. During IVCY therapy, the patient experienced blurred vision in the right eye, and this was diagnosed as being due to CRAO and CRVO. However, the patient did not manifest any embolic, coagulopathic, or vasculitic symptoms, and there were no abnormal laboratory data suggesting these diseases in relation to this symptom. Therefore, the ocular occlusion was presumed to be due to MIT of small arteries, in addition to severe Raynaud’s phenomenon. Thus, we report the findings of this important case, despite the fact that it lacks a retinal pathology.

Bilateral anterior ischaemic optic neuropathy with macular star as first manifestation of Henoch‐Schönlein purpura (IgA vasculitis)

AbstractPurposeTo report a case of bilateral anterior ischaemic optic neuropathy with macular star in a patient with Henoch–Schönlein purpura (HSP).MethodsA 46‐year‐old man was referred to our clinic complaining of progressive decrease in visual acuity of the right eye (OD) since the last 10 days, and since 3 days in his left eye (OS). His visual acuity was ‘hand motion’ OD and 4/10 OS. Anterior segment examination was insignificant, while fundus examination revealed optic disc edema, and bilateral macular star. A relative afferent pupillary defect was present in his right eye with normal pupillary reflexes in the left eye. Laboratory analysis showed: Hematocrit: 22.1%, ESR: 140 mm/hr, CRP: 64.80 mg/dl, Creatinine: 4.4 mg/dl. Physical examination revealed presence of erythematous rash on the trunk and the extremities. The patient was admitted to the Nephrology department for treatment of his azotemia.ResultsDuring his hospital course we performed complete laboratory and imaging examinations for autoimmune diseases, vasculitis and infectious diseases, which were negative. Histologic findings of renal biopsy were compatible with IgA glomerulonephritis and thus HSP was diagnosed. The patient received oral methylprednisolone and intravenous cyclophosphamide therapy. Six months later his renal function had improved, the rash had subsided and his visual acuity was ‘counting fingers’ OD and 10/10 OS. Standard automated perimetry showed peripheral visual field depression bilaterally.ConclusionsHenoch–Schönlein purpura (HSP) is a small vessel vasculitis which is more common in children. Based on literature, ophthalmic manifestations of HSP usually involve the anterior segment and less frequently the posterior segment. Systemic vasculitis should be included in the differential diagnosis of bilateral optic disc edema.

47. Claudication, Cerebral infarct and Cyclophosphamide

IntroductionWe present a severe and rare case of GCA involving the right middle cerebral artery (MCA) resulting in an ischaemic stroke. Our patient presented in 2017, before tocilizumab was approved as a treatment option in refractory GCA. Intravenous cyclophosphamide was used as a glucocorticoid-sparing agent in this patient with good response. This case contributes to our current limited evidence base in the treatment and prognosis of intracranial GCA.Case descriptionThe patient was 75 years old when referred by his GP with a four-month history of left temporal headache, jaw claudication and weight loss in August 2017. He had type 2 diabetes and hypertension. He also had a stroke in 2015 and was subsequently found to have paroxysmal atrial fibrillation so was commenced on rivaroxaban. His bloods showed ESR of 66 and CRP 18. ESR had been persistently raised for two months. Ophthalmology assessment revealed bilateral cataracts only. A clinical diagnosis of GCA was made and he was commenced on prednisolone 60mg daily. A biopsy of his left temporal artery was performed six days later and the histology showed transmural inflammation with multinucleated giant cells. His headache and jaw claudication improved with prednisolone but he was still experiencing localised temporal artery tenderness. In the last week of September 2017, he presented to the Emergency Department with a two-day history of incoordination and left arm weakness. MRI of his head showed small foci of infarcts in the right MCA territory. He had suffered an ischaemic stroke likely secondary to GCA despite being treated with high dose oral glucocorticoid. He was given three pulses of intravenous methylprednisolone followed by intravenous cyclophosphamide.Subsequent CT angiogram (CTA) confirmed the involvement of intracranial arteries – circumferential thickening of the right internal carotid artery with near complete occlusion of right cavernous and intracranial segments. There was also mural thickening involving the left vertebral artery. He went on to have five more cycles of cyclophosphamide and responded well to treatment. Oral methotrexate 15mg weekly was added in two weeks after the last course of cyclophosphamide. During his last clinic visit, he was taking prednisolone 2mg daily and the plan was to taper the dose down to zero over eight weeks.DiscussionThough uncommon, GCA can affect vertebrobasilar arteries causing strokes. The involvement of intracranial arteries, on the other hand, is thought to be extremely uncommon in GCA due to their increased wall thickness. There is only a limited number of intracranial GCA cases reported in the medical literature. A review of nearly 500 patients with a diagnosis of central nervous system vasculitis at the Mayo Clinic identified only two patients with convincing evidence of intracranial GCA.Our patient’s MRI and CTA were reviewed in the neuroradiology multidisciplinary meeting and the consensus was that there was a near complete occlusion of the right MCA due to a vasculitic process. Importantly, his GCA went into remission and he has not had any relapses thus far (21 months since his initial presentation). He has also improved from the stroke point of view. We have been able to reduce his prednisolone dose to a minimal level.The use of oral or intravenous cyclophosphamide in the treatment of refractory GCA have been reported. It was found to be effective in inducing a sustained remission in a majority of patients in a series of 35 patients in Germany. However, significant adverse events were reported in one third of the patients.Our patient tolerated intravenous cyclophosphamide therapy well. He was given fluconazole and co-trimoxazole as prophylactics. He did not report any major infections or adverse events during the four-month period when he was on cyclophosphamide.Key learning pointsThis case represents a severe variant of GCA. Our patient was only referred to secondary care after being unwell for several months. It illustrates the importance of promptly initiating investigations and treatment when GCA is suspected. This case demonstrates the importance of following up with patients closely as well as working closely with the multispecialty team in managing patients with GCA. Conflicts of interestThe authors have declared no conflicts of interest.

Intravenous Cyclophosphamide Therapy for Anti-IFN-Gamma Autoantibody-Associated Mycobacterium abscessus Infection.

Introduction Anti-interferon-gamma (IFN-γ) autoantibodies are increasingly recognized as a cause of adult-onset immunodeficiency (AOID) worldwide. These patients are susceptible to various intracellular pathogens especially nontuberculous mycobacteria. Most of the patients have a refractory clinical course. Herein, we report the use of immunotherapy with pulse intravenous cyclophosphamide (IVCY) in patients who had progressive, refractory Mycobacterium abscessus infection. Method We included patients, seen at Srinagarind Hospital, Thailand, infected with M. abscessus, who had received ≥3 courses of parenteral antibiotics within the last 12 months and who received pulse IVCY with a tapering dose of prednisolone. Results There were 8 AOID patients who met the criteria and received pulse IVCY between January 2011 and December 2015. One patient was lost to follow-up after 5 courses of IVCY: he had died at home 3 months later. Five patients had favorable outcomes: 2 were able to discontinue NTM therapy, and 3 had stable disease and were on NTM treatment without hospitalization for parenteral antibiotics. Two patients relapsed and needed hospitalization. The IFN-γ Ab titers among the 7 patients were significantly decreased during treatment, and the median initial antibody titer started at 200,000 and then decreased to 5,000 after 2 years of treatment (P < 0.0001). The antibody titer reduction among responsive vs. nonresponsive patient was significantly different after 6 months of treatment: the median antibody titer was 5,000 and 100,000, respectively (P = 0.0467). Conclusion IVCY therapy might be an alternative treatment for AOID patients infected with M. abscessus and refractory to antimycobacterial therapy.

Case 259.

History In November 2012, a previously healthy 31-year-old woman was admitted to our hospital with a 2-month history of right-sided numbness, diplopia, and intermittent nausea and dizziness. She did not have a history of fever, weight loss, headache, photophobia, seizure, or extremity weakness. Physical examination revealed left abduction limitation and right-sided hypoesthesia. Kernig and Brudzinski signs were absent, and pathergy test results were negative. Laboratory evaluation revealed normal complete and differential blood counts, normal serum chemistry, and normal immune function. Analysis of her serum was negative for antiaquaporin 4 antibody, rheumatism antibody profile, and paraneoplastic profile. Serum analysis was also negative for human immunodeficiency virus type 1 and 2 RNA, hepatitis B and C antigen or antibody profile, and fluorescent treponemal antibody absorption. Cerebrospinal fluid (CSF) analysis revealed clear fluid, a normal glucose level, an elevated protein level (45 mg/dL; normal range, 20-40 mg/dL), and an elevated white blood cell count (10/mm3 [0.01 ×109/L]; normal range, 0-8/mm3 [{0-0.008} ×109/L]; 81% lymphocytes, 19% monocytes). No CSF-specific oligoclonal bands were detected. Gram staining, acid-fast staining, and lactic acid and cryptococcal antigen test results were negative. CSF did not grow any bacteria, fungus, or acid-fast bacillus at culture. Spinal cord MRI, brain MR angiography, and CT of the chest, abdomen, and pelvis revealed normal findings (images not shown). Brain MRI and gadolinium-enhanced (20 mL gadopentetate dimeglumine, BeiLu Pharmaceutical, Beijing, China) MRI were performed ( Fig 1 ). The patient's clinical symptoms and imaging findings responded to treatment with a high dose of steroids. However, the patient's symptoms exhibited clinical and radiologic progression as she attempted to taper the steroid dose. She arbitrarily stopped taking the steroids and started traditional Chinese treatment instead. However, her condition was not controlled. [Figure: see text][Figure: see text][Figure: see text] In November 2013, she was readmitted with worsening dizziness and diplopia accompanied by hearing loss, tinnitus, slurred speech, drinking-induced cough, walking instability, and involuntary outbursts of laughter and crying. Dysmetria, ataxia, brisk tendon reflexes, pathologic reflexes, and pseudobulbar signs were observed bilaterally. Repeated biochemical and immune tests did not yield positive findings. CSF analysis revealed mild lymphocytic pleocytosis (white blood cell count, 8/mm3 [0.008 ×109/L]; 83% lymphocytes, 17% monocytes) and a slightly elevated total protein level (46 mg/dL). Brain PET revealed diffuse high metabolism in the midbrain and pons (images not shown). Whole-body PET was negative for malignancy (images not shown). Brain MRI and gadolinium-enhanced MRI were performed ( Fig 2 ). The patient's clinical symptoms and imaging findings improved after treatment with a high dose of steroids. Thereafter, intravenous cyclophosphamide therapy was added after her condition deteriorated again when the prednisone dose was tapered to 20 mg per day in March 2014 ( Fig 3a ). Her pontocerebral symptoms were relatively stable in the following year, with apparent diminishment of lesions in the brainstem and cerebellum observed at brain PET (images not shown). Follow-up MR images were obtained in July 2014 ( Fig 3b ). Subsequently, the patient exhibited clinical and radiologic aggravation. MR images were obtained again in July 2015 ( Fig 4 ) and February 2016 ( Fig 5 ). The patient underwent biopsy of the right frontal lobe, and a histopathologic examination was performed in August 2015. Afterward, her condition worsened, and she died in September 2016. [Figure: see text][Figure: see text][Figure: see text] [Figure: see text][Figure: see text].

Risk factors for infectious complications of ANCA-associated vasculitis: a cohort study

BackgroundSevere infections are common complications of immunosuppressive treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with renal involvement. We investigated the clinical characteristics and risk factors of severe infection in Chinese patients with AAV after immunosuppressive therapy.MethodsA total of 248 patients with a new diagnosis of ANCA-associated vasculitis were included in this study. The incidence, time, site, and risk factors of severe infection by the induction therapies were analysed. Multivariate Cox proportional hazards models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CI).ResultsA total of 103 episodes of severe infection were identified in 86 (34.7%, 86/248) patients during a median follow-up of 15 months. The incidence of infection during induction therapy was 38.5% for corticosteroids (CS), 39.0% for CS+ intravenous cyclophosphamide (IV-CYC), 33.8% for CS+ mycophenolate mofetil and 22.5% for CS + tripterygium glycosides, 76 (73.8%) infection episodes occurred within 6 months, while 66 (64.1%) occurred within 3 months. Pneumonia (71.8%, 74/103) was the most frequent type of infection, and the main pathogenic spectrum included bacteria (78.6%), fungi (12.6%), and viruses (8.7%). The risk factors associated with infection were age at the time of diagnosis (HR = 1.003, 95% CI = 1.000–1.006), smoking (HR = 2.338, 95% CI = 1.236–4.424), baseline secrum creatinine (SCr) ≥5.74 mg/dl (HR = 2.153, 95% CI = 1.323–3.502), CD4+ T cell< 281 μl (HR = 1.813, 95% CI = 1.133–2.900), and intravenous cyclophosphamide regimen (HR = 1.951, 95% CI =1.520–2.740). Twelve (13.9%) patients died of severe pneumonia.ConclusionThe infection rate during induction therapy was high in patients with AAV. Bacterial pneumonia was the main type of infection encountered. Age at the time of diagnosis, smoking, baseline SCr ≥5.74 mg/dl, CD4+ T cell< 281 μl, and IV-CYC therapy were identified as risk factors for infection.

Effect of a gonadotropin-releasing hormone analog for ovarian function preservation after intravenous cyclophosphamide therapy in systemic lupus erythematosus patients: a retrospective inception cohort study.

To determine the effect of leuprolide acetate, a synthetic gonadotropin-releasing hormone analog (GnRH-a) on ovarian function preservation in systemic lupus erythematosus (SLE) patients treated with cyclophosphamide (CYC) in clinical practice. We enrolled 30 premenopausal female SLE patients who fulfilled the 1997 American College of Rheumatology revised criteria and were treated with intravenous CYC (IVCY) in 2008-2017. We used Kaplan-Meier survival estimates to compare the GnRH-a-treated patients and those not treated with GnRH-a as controls. We performed Cox regression analyses to identify factors associated with premature ovarian failure (POF), incidences of cardiovascular events, strokes and osteoporosis after IVCY therapy. After a mean follow-up of 41months, POF developed in one of the 16 GnRH-a-treated patients (6%) versus seven of the 14 controls (50%). Significantly improved cumulative ovarian protection over time was observed in the GnRH-a-treated group (P=0.030). The hazard model analysis showed that treatment with GnRH-a during IVCY therapy is an independent factor associated with POF after IVCY therapy (adjusted hazards ratio=0.12, 95% CI 0.01-0.67, P=0.013) but not incidences of cardiovascular events, strokes or osteoporosis. The combined use of GnRH-a with IVCY therapy was associated with a significant reduction of POF among premenopausal women with SLE, suggesting that the addition of GnRH-a can be a strategy to prevent POF among premenopausal women with SLE after IVCY therapy.

Late restoration of renal function in patients with severe ANCA-associated glomerulonephritis who were dialysis-dependent at presentation.

In antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), many patients with severe renal dysfunction are on dialysis at presentation. Among those who got rid of dialysis finally, renal restoration happened mostly within the first 3months of treatment. However, in clinical practice, we occasionally encountered patients who got rid of dialysis after 3months. The current study investigated clinical and pathological features of AAV patients with so-called delayed renal function restoration. A total of 156 patients with ANCA-associated glomerulonephritis who were on dialysis at presentation were retrospectively recruited. Clinical and pathological data as well as treatment and outcomes were analyzed. Among these 156 patients, 58 and 12 patients got rid of dialysis within and after 3months, respectively. Among the 12 patients with delayed renal function restoration, 8 and 4 patients got rid of dialysis within and after 6months, respectively. Among the 72 patients who were still on dialysis at the end of 3months since the initiation of immunosuppressive therapy, those receiving intravenous cyclophosphamide therapy over 3months had significantly higher proportion of renal function restoration than those receiving intravenous cyclophosphamide for only 3months (8/14 versus 4/58, P < 0.001). For patients with ANCA-associated glomerulonephritis who were on dialysis at presentation, there is an unnegligible proportion of patients who had their renal function restoration beyond 3months since the initiation of immunosuppressive therapy. Further studies are needed to investigate whether, and for whom, cyclophosphamide prescription should be prolonged for more than 3months.

Pulmonary lymphangioleimyomatosis and systemic lupus erythematosus in a menopausal woman

BackgroundPulmonary lymphangioleimyomatosis (PLAM) is a rare disease involving lung. PLAM primarily affects young women, a characteristic it shares with systemic lupus erythematosus (SLE). Estrogen has long been assumed to play an important role both in PLAM and SLE. We report a menopausal woman, who was found to have PLAM 1 year after she was diagnosed with SLE. Her chest radiograph was normal in the early phase of SLE.Case presentationA 52-year-old Chinese woman was referred to our hospital in August 2014 because of swelling in both legs. She also reported a malar rash and intermittent generalized arthralgia. Laboratory examination showed leukopenia. Her serum albumin level was 23 g/L; 24-h urinary protein excretion was 5.3 g. She tested positive for anti-Smith (Sm) antibody and anti-SS-A antibody. Renal biopsy indicated Class V + IV(G)-A lupus nephritis (LN). The condition of SLE and LN improved on a regime of tapering prednisolone and intermittent intravenous cyclophosphamide therapy until 1 year later when she developed exertional dyspnea accompanied with frequent cough. Thoracic computed tomography revealed numerous well-defined cysts and the diagnosis of PLAM was confirmed by lung biopsy. In the follow-up period, the patient continued to be on prednisolone and mycophenolate mofetil for the treatment of SLE, but only agreed to receive symptomatic treatment for PLAM. One year after the diagnosis of PLAM, during which time the SLE was stable, she died of respiratory failure and cor pulmonale.ConclusionWe report a patient with coexisting SLE and PLAM, who was treated with immunosuppressive therapy. SLE was stable but PLAM was not improved. Although the coexistence of SLE and PLAM might be a coincidence, the occurrence of these two diseases in a menopausal woman may warrant further mechanistic exploration.

Successful treatment of plasma exchange for rapidly progressive interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis

Rationale:As the initial treatment of rapidly progressive interstitial lung disease (RPILD) with antimelanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab)-positive dermatomyositis (DM) patients, a combination of corticosteroids, cyclophosphamide, and calcineurin inhibitor is recommended. However, some of these patients have poor prognoses despite such intensive treatment. Other more effective treatments are desired. We report the case of an anti-MDA5 Ab-positive DM patient who had developed RPILD despite intensive treatments; she was treated successfully by a short-term plasma exchange (PE).Patient concerns:A 71-year-old Japanese woman was admitted to the rheumatology department of another hospital with progressive muscle weakness of the limbs and erythema on both upper eyelids and the fingers of both hands. She was suspected of having classical DM (CDM) based on the findings of typical skin and myositis. Although a chest computed tomography (CT) examination showed no findings of interstitial pneumonia at the first visit to the department, she newly presented interstitial pneumonia during her admission and her anti-MDA5 Ab titer was elevated.Diagnoses:She was diagnosed with interstitial lung disease (ILD) with anti-MDA5 Ab-positive DM.Interventions:She was treated with 1000 mg of methyl-prednisolone pulse, 500 mg of intravenous cyclophosphamide therapy (IVCY) followed by prednisolone 40 mg/day with tapering, and oral cyclosporine 200 mg/day. However, her interstitial pneumonia worsened with increasing breathing difficulty and an increasing serum ferritin level. She was transferred to our department, and we initiated PE as an additional treatment.Outcomes:After the PE treatment, all laboratory findings, for example, ferritin, KL-6, and the titer of anti-MDA5 Ab showed marked improvement, and the patient's skin symptoms and active interstitial pneumonia were relieved.Lessons:Our patient's case suggests that PE may be effective for RPILD in anti-MDA5 Ab-positive DM patients.

Intravenous pulsed vs oral cyclophosphamide therapy in steroid dependent nephrotic syndrome

Background: No consensus exists concerning dose and route of administration of cyclophosphamide (CYC) in steroid-dependant nephrotic syndrome (SDNS). Objective: To compare the outcome of children with SDNS treated with either intravenous (IV) or oral CYC in a single centre in Sri Lanka by reviewing data from 2002 to 2011. Method: One hundred and twenty seven children with SDNS with evidence of steroid toxicity received either oral or IV cyclophosphamide. Seventy two received IV cyclophosphamide in a dose of 500 mg/m 2 monthly for 6 months, and 55 received oral CYC in a dose of 3 mg/kg per day for 8 weeks. In both groups prednisolone was tapered over 6 months in a similar manner. Full blood counts were done weekly during oral treatment and monthly during IV treatment. Patient progress was assessed on a monthly basis for the first year and at 3 monthly intervals thereafter till 5 years. Results: In the oral CYC group, 4 patients developed bone marrow suppression, 7 had serious infections, 15 had significant alopecia and one child died due to overwhelming sepsis. In the IV group alopecia was seen in 9 patients and one had a serious infection while bone marrow suppression was not seen. At one and 5 year follow ups there was no significant difference in the proportion who suffered a relapse in the 2 groups (p >0.05) Conclusion: In SDNS, IV cyclophosphamide was as effective as oral CYC in inducing sustained remission and had less side effects and a smaller total dose. Sri Lanka Journal of Child Health , 2017; 46 (4): 317-321

Dermatomyositis Leading to Necrotizing Vasculitis: A Perfect Response to Applied Therapy

Dermatomyositis is an idiopathic inflammatory myopathy that cause skin and muscle complications. The ethiology is not understood well yet. Released cytokines including interferon and interleukins are suggested to make inflammatory responses in the skin or muscle. Muscle weakness and skin lesions including heliotrope rash, shawl sign and Gottron's papules are the most common symptoms. A biopsy (muscle or skin) is always the most reliable method for diagnosis. Corticosteroids in association with immunosuppressive agents are used as standard treatment. The patient was a 30 years old woman who got involved with dermatomyositis for 10 years. She has been under therapy with Methotrexate, Prednisolon and Azathioprine until she came to us suffering from progressive skin lesions. Experiments and examinations were normal except the lesions and detected lipoatrophy. Because of immune cells infiltration and observations necrotizing vasculitis was diagnosed. After three month of high dose prednisolon and intravenous cyclophosphamide therapy the lesions vanished remarkable. True and immediate diagnosis gives physicians the chance not only to assess the best treatment but have adequate time to apply the procedure. However shortening the therapy and diminishing morbidity of the disease need more investigations and efforts.