High-dose Intravenous Glucocorticoids Research Articles

Sudden Visual Loss due to Arteritic Anterior Ischaemic Optic Neuropathy: A Rare Manifestation of Eosinophilic Granulomatosis with Polyangiitis.

eosinophilic granulomatosis with polyangiitis (EGPA) is a rare multisystem inflammatory disease characterized by asthma, eosinophilia and granulomatous or vasculitic involvement of various organs. While the eye is uncommonly affected in patients with EGPA, multiple ophthalmic manifestations have been reported, which can result in serious visual impairment without timely treatment. we report the case of a 79-year-old woman with a history of asthma and nasal polyps who presented with low-grade fever, mild alteration of mental status, and fatigue. Chest X-ray revealed bilateral interstitial infiltrates. Lab tests showed elevated C-reactive protein level and eosinophilia (eosinophil count, 4.6 x109 cells/l); blood cultures and parasitological examination of stools tested negative. Four days after presentation, the patient reported sudden and severe blurring of vision in her left eye. Ophthalmological examination revealed bilateral swollen optic disc and visual field loss, more severe in the left eye. A diagnosis of EGPA complicated by arteritic anterior ischaemic optic neuropathy (A-AION) was proposed, while an alternative or concurrent diagnosis of giant cell arteritis was ruled out based on clinical picture. Immunosuppressive treatment with high-dose intravenous glucocorticoids was promptly started. The patient's visual defect did not improve; however, two months later, no worsening was registered on ophthalmic reassessment. A-AION is an infrequent but severe manifestation of EGPA, requiring prompt diagnosis and emergency-level glucocorticoid therapy to prevent any further vision loss. Disease awareness and a multidisciplinary approach are crucial to expedite diagnostic work-up and effective management of EGPA-related ocular complications. Arteritic ischaemic optical neuropathy is a potential cause of sudden and severe visual loss in eosinophilic granulomatosis with polyangiitis (EGPA) patients.Visual loss due to arteritic ischaemic optical neuropathy is rarely reversible; however, a timely glucocorticoid treatment may prevent further progression of visual impairment.Multidisciplinary approach is crucial to expedite diagnostic work-up and effective management of EGPA patients with ocular complications.

Part II: Interactive case: Drug‐induced endocrine disorders

Part <scp>II</scp>: Interactive case: <scp>Drug‐induced</scp> endocrine disorders

Postdischarge Glucocorticoid Use and Clinical Outcomes of Multisystem Inflammatory Syndrome in Children

Minimal data are available regarding the postdischarge treatment of multisystem inflammatory syndrome in children (MIS-C). To evaluate clinical characteristics associated with duration of postdischarge glucocorticoid use and assess postdischarge clinical course, laboratory test result trajectories, and adverse events in a multicenter cohort with MIS-C. This retrospective cohort study included patients with MIS-C hospitalized with severe illness and followed up for 3 months in an ambulatory setting. Patients younger than 21 years who were admitted between May 15, 2020, and May 31, 2021, at 13 US hospitals were included. Inclusion criteria were inpatient treatment comprising intravenous immunoglobulin, diagnosis of cardiovascular dysfunction (vasopressor requirement or left ventricular ejection fraction ≤55%), and availability of complete outpatient data for 3 months. Glucocorticoid treatment. Main outcomes were patient characteristics associated with postdischarge glucocorticoid treatment, laboratory test result trajectories, and adverse events. Multivariable regression was used to evaluate factors associated with postdischarge weight gain (≥2 kg in 3 months) and hyperglycemia during illness. Among 186 patients, the median age was 10.4 years (IQR, 6.7-14.2 years); most were male (107 [57.5%]), Black non-Hispanic (60 [32.3%]), and Hispanic or Latino (59 [31.7%]). Most children were critically ill (intensive care unit admission, 163 [87.6%]; vasopressor receipt, 134 [72.0%]) and received inpatient glucocorticoid treatment (178 [95.7%]). Most were discharged with continued glucocorticoid treatment (173 [93.0%]); median discharge dose was 42 mg/d (IQR, 30-60 mg/d) or 1.1 mg/kg/d (IQR, 0.7-1.7 mg/kg/d). Inpatient severity of illness was not associated with duration of postdischarge glucocorticoid treatment. Outpatient treatment duration varied (median, 23 days; IQR, 15-32 days). Time to normalization of C-reactive protein and ferritin levels was similar for glucocorticoid duration of less than 3 weeks vs 3 or more weeks. Readmission occurred in 7 patients (3.8%); none was for cardiovascular dysfunction. Hyperglycemia developed in 14 patients (8.1%). Seventy-five patients (43%) gained 2 kg or more after discharge (median 4.1 kg; IQR, 3.0-6.0 kg). Inpatient high-dose intravenous and oral glucocorticoid therapy was associated with postdischarge weight gain (adjusted odds ratio, 6.91; 95% CI, 1.92-24.91). In this multicenter cohort of patients with MIS-C and cardiovascular dysfunction, postdischarge glucocorticoid treatment was often prolonged, but clinical outcomes were similar in patients prescribed shorter courses. Outpatient weight gain was common. Readmission was infrequent, with none for cardiovascular dysfunction. These findings suggest that strategies are needed to optimize postdischarge glucocorticoid courses for patients with MIS-C.

High-dose intravenous glucocorticoid induces hyperamylasemia: a case series

BackgroundGlucocorticoids have many side effects, and high-dose intravenous application may cause rare adverse reactions such as hyperamylasemia. The aim of this study is to explore the clinical characteristics, treatment, and prognosis of hyperamylasemia induced by high-dose intravenous glucocorticoids.Case presentationFour Asian female patients, aged between 26 and 71 years, were diagnosed with hyperamylasemia after intravenous administration of high-dose glucocorticoid. Amylase levels were elevated to varying degrees in all patients, but the peaks were below three times the upper limit of normal, and imaging showed no significant pancreatic abnormalities. Two patients developed abdominal pain, which was resolved by inhibition of pancreatic secretion, while the other patients were asymptomatic. Two patients were discharged after a significant decrease in amylase levels, while the other two were discharged after improvement of the primary disease.ConclusionHigh-dose intravenous glucocorticoid can cause hyperamylasemia, which should be given enough attention by clinicians. Etiological differentiation of hyperamylasemia should be emphasized in clinical practice, especially when the diagnosis of acute pancreatitis is not clear.

Unveiling Deficiency of Adenosine Deaminase 2: An Adult Patient With Recurrent Strokes, Vasculitic Ulcers, and Bowel Perforation.

Here we describe the case of a 38-year-old man with a history of ischemic transient attacks and strokes from the age of 9 years, livedo reticularis, asymmetrical sensorimotor neuropathy, optic neuritis, testicular ischemia, digital ulcers, ulcerative colitis, and diastolic hypertension. Disease course was characterized by severe disease bouts treated with high-dose intravenous (IV) glucocorticoid (GC) pulse therapy, short periods of paucisymptomatic disease, and inability to taper GCs despite the use of traditional oral and IV immunosuppressants, interferon, and plasmapheresis.

ACUTE EOSINOPHILIC PNEUMONIA: COMPLICATIONS OF SMOKE EXPOSURE AND VAPING-ASSOCIATED LUNG INJURY

TOPIC: Occupational and Environmental Lung Diseases TYPE: Medical Student/Resident Case Reports INTRODUCTION: E-cigarette or vaping product use-associated lung injury (EVALI) encompass a host of pulmonary complications including diffuse alveolar hemorrhage, lipoid pneumonia, hypersensitivity pneumonitis, and rarely, acute eosinophilic pneumonia (AEP) [1]. AEP presents as an acute febrile illness with hypoxemia, diffuse pulmonary infiltrates, and eosinophilia on bronchoalveolar lavage (BAL) without evidence of prior infection or atopic illness [2]. Presented is a young adult patient with a history of continuous vaping and extended exposure to kitchen smoke who developed acute hypoxemic respiratory failure later diagnosed as AEP. CASE PRESENTATION: An 18-year-old male with no significant past medical history presented to the emergency department with acute onset malaise, fever, non-productive cough, and shortness of breath over 12 hours. Social history revealed 3-week workplace exposure to smoke as a barbeque cook and a 5-year history of daily vaping with reported cessation 3 weeks prior. Vitals were notable for hypoxemia which was corrected with administration of 8L of oxygen via nasal cannula. Quickly after admission, he had worsening respiratory status: tachypnea, increased oxygen requirement, use of accessory muscles, and bilaterally diminished breath sounds. He was transferred to the medical intensive care unit for emergent endotracheal intubation. Laboratory testing revealed a neutrophil predominant leukocytosis of 19.3x109/L. COVID-19, rapid influenza A and B, and urine antigens for streptococcus and legionella were negative as were autoimmune serologies. A computed tomography (CT) scan of the chest revealed diffuse bilateral consolidative opacities [Figure 1] with worsening over the next 24 hours [Figure 2]. Further investigation was undertaken with bronchoscopy. A BAL was obtained, and cell count and cultures were sent. BAL cell count was remarkable for 33% eosinophilia. The diagnosis of AEP was made, and the patient was started on systemic glucocorticoids, with significant improvement within 24 hours. DISCUSSION: The modified Philit criteria is used to make the diagnosis of AEP, which the patient satisfied [3]. Although a 5-year vaping history was present, no previous significant respiratory symptoms were reported. Prior studies have demonstrated a relationship between workplace smoke exposure and AEP [3]. Based on the modified Philit criteria, we suspect that the patient had acute respiratory failure from AEP as a result of chronic EVALI acutely exacerbated by workplace smoke exposure. The treatment of AEP treatment involves high-dose intravenous glucocorticoids followed by a prolonged oral steroid taper. CONCLUSIONS: Obtaining occupation history as well as smoke exposure is as important as obtaining vaping history in an otherwise healthy young patient who presents with acute hypoxemic respiratory failure with bilateral diffuse opacities on imaging. REFERENCE #1: Winnicka L, Shenoy MA. EVALI and the Pulmonary Toxicity of Electronic Cigarettes: A Review. J Gen Intern Med. 2020;35(7):2130-2135. doi:10.1007/s11606-020-05813-2 REFERENCE #2: Allen JN, Pacht ER, Gadek JE, Davis WB. Acute Eosinophilic Pneumonia as a Reversible Cause of Noninfectious Respiratory Failure. N Engl J Med. 1989;321(9):569-574. doi:10.1056/nejm198908313210903 REFERENCE #3: Philit F, Etienne-Mastroïanni B, Parrot A, Guérin C, Robert D, Cordier JF. Idiopathic acute eosinophilic pneumonia: A study of 22 patients. Am J Respir Crit Care Med. 2002;166(9):1235-1239. doi:10.1164/rccm.2112056 DISCLOSURES: No relevant relationships by Nurjahan Khatun, source=Web Response No relevant relationships by Parth Patel, source=Web Response No relevant relationships by Naleen Patel, source=Web Response No relevant relationships by Tarang Patel, source=Web Response No relevant relationships by SACHIN PATIL, source=Web Response No relevant relationships by Shyam Shankar, source=Web Response No relevant relationships by Rodger Wilhite, source=Web Response

Ocrelizumab-induced inflammatory bowel disease-like illness characterized by esophagitis and colitis

Ocrelizumab is an intravenous anti-CD20 monoclonal antibody, approved for use in primary progressive multiple sclerosis due to its selective depletion of B-lymphocytes. Herein we describe the case of a 56-year-old female who developed odynophagia and bloody diarrhea following treatment with ocrelizumab. This was characterized endoscopically by ulcerations in the esophagus and colon. The patient was treated with high-dose intravenous glucocorticoids with good clinical response.

Fulminant Acute Disseminated Encephalomyelitis: A Remarkable Outcome with Cyclophosphamide

AbstractAcute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system which occurs predominantly in the pediatric population. Acute treatment is high-dose intravenous glucocorticoids. Alternative treatment is usually intravenous immune globulin and/or plasma exchange. Fulminant ADEM is rare in children. Only a few cases of cyclophosphamide use in refractory ADEM have been reported. Here, we report a case of a 12-year-old girl with fulminant ADEM who was comatose and improved dramatically after cyclophosphamide administration. Cyclophosphamide treatment should be considered as a therapy in children with fulminant ADEM nonresponsive to standard therapies.

Cholesterol Serum Levels and Use of Statins in Graves' Orbitopathy: A New Starting Point for the Therapy.

Graves' Orbitopathy (GO) is the most frequent extrathyroidal manifestation of Graves' disease (GD). Its ultimate cause remains unclear, but it is commonly considered an autoimmune disorder due to self recognition of autoantigens constitutively expressed by orbital fibroblasts (OFs), and thyroid epithelial cells. High dose intravenous glucocorticoids (ivGC) are the most commonly used treatment for moderately severe and active GO. However, based on the complex pathogenesis of GO, a number of factors may have a protective and maybe a therapeutic role. The use of other medications improving the effect of GC may increase the overall effectiveness of the therapy and reduce GC doses, thereby limiting side effects. Recently, a possible protective role of 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors, the so-called statins, and perhaps of lowering cholesterol levels, has been proposed. Thus, statins have been reported to be associated with a reduced frequency of GO in GD patients and in recent cross-sectional and retrospective studies a significant correlation was found between the occurrence of GO and both total and LDL-cholesterol in patients with a GD of relatively recent onset, suggesting a role of cholesterol in the development of GO. Moreover, a correlation was found between the GO clinical activity score and total as well as LDL-cholesterol in untreated GO patients, depending on GO duration, indicating a role of cholesterol on GO activity. Therefore, statin treatment may be beneficial for GO. Here we review this subject, which offers new therapeutic perspectives for patients with GO.

Intravenous glucocorticoids therapy in the treatment of Graves' ophthalmopathy: a systematic review and Meta-analysis.

To evaluate the benefit and harms of high-dose intravenous glucocorticoids (IVGC) as first-line treatment for Graves' ophthalmopathy (GO). A systematic review and Meta-analysis of randomized clinical trials (RCTs) comparing IVGC for the treatment of GO, with placebo or other treatments, were conducted. Electronic databases were searched, and standard methodological guidance of Cochrane Handbook for Systematic Reviews of Interventions was used. The primary outcome was overall response, and secondary outcomes included the improvement and change in clinical activity score (CAS), and adverse events. Ten RCTs were included in the Meta-analysis. Low quality evidence (one trial) showed that participants receiving IVGC achieved significantly higher response compared to participants receiving placebo [risk ratio (RR) 7.50, 95% confidence interval (CI) 1.14 to 49.26]. Moderate quality evidence (four trials) support appreciable benefit of IVGC in response compared with oral glucocorticoids (OGC), with of RR being 1.51 (95%CI 1.25 to 1.83). There was low quality evidence (one trial) compatible with appreciable benefit for IVGC plus orbital radiotherapy in response (RR 1.38, 95%CI 1.07 to 1.79), compared with OGC plus orbital radiotherapy. One IVGC versus rituximab trial provided moderate quality evidence suggesting that participants using IVGC achieved significantly lower response compared to participants using rituximab (RR 0.70, 95%CI 0.50 to 0.98). One IVGC versus mycophenolate mofetil (MMF) trial provided moderate quality evidence suggesting that participants using IVGC achieved significantly lower response compared to participants using MMF (RR 0.74, 95%CI 0.63 to 0.88). Very low quality evidence (one trial) showed that participants with dysthyroid optic neuropathy (DON) receiving IVGC were more likely to achieve response compared to participants receiving orbital decompression (RR 3.33, 95%CI 0.51 to 21.89). The current evidence is moderate quality, which is sufficient to support IVGC to be as the first-line treatment for moderate-to-severe GO, and the use of rituximab or MMF to be the second-line treatment instead of IVGC. However, the evidence is very low quality, which is insufficient to support the use of IVGC or orbital decompression as the first-line treatment of DON.

Intravenous Glucocorticoid Pulse Therapy in Active, NSAID Refractory Axial An

Objective: High dose intravenous glucocorticoid (IVGC) pulse therapy is known to effectively reduce inflammatory signs and symptoms in patients with active inflammatory conditions. However, the efficacy of IVGC in ankylosing spondylitis (AS) is not clearly established. Methods: We performed a retrospective analysis with repeated measurements including patients with active, NSAID refractory axial AS (n=15) who underwent high dose IVGC pulse therapy. Parameters of clinical and humoral disease activity were compared to active AS patients (n=14) under continuous anti-TNF treatment. Patients were seen every 3 months and followed up for a total period of 12 months. Results: Both IVGC pulse and anti-TNF therapy lead to a significant and sustained reduction of the mean bath ankylosing spondylitis disease activity index (BASDAI 7.4 ± 1.5 at baseline vs. 5.4 ± 2.1 at 12 months in the pulse group and 6.9 ± 1.2 at baseline vs. 5.0 ± 2.7 at 12 months in the anti-TNF group, p<0.001), CRP (p=0.018), ESR (p=0.028), morning stiffness (p<0.001), and finger-to-floor-distance (p=0.001; within group comparison). Conclusions: Patients with active axial AS treated with one IVGC pulse show a substantial decrease in disease activity over a period of 12 months in this retrospective analysis.

Effect of intravenous pulse dexamethasone versus daily oral prednisolone on bone mineral density in dermatology patients: Is it a site-specific response?

The use of glucocorticoids in various forms of administration is complicated by their systemic side effects. Although intravenous pulse therapy is considered to have lesser systemic side effects, there are few studies in literature comparing the effects of intravenous pulse glucocorticoids versus oral daily glucocorticoids on bone mineral density. To compare the effects of intravenous pulse glucocorticoids and oral daily glucocorticoids on bone mineral density with the aim of finding any site-specific osteopenic side effect. The study was conducted by the department of dermatology of Postgraduate Institute of Medical Education and Research, Chandigarh, India. The study comprised of two groups of patients. Group A consisted of 28 patients with pemphigus vulgaris who received intravenous pulses of dexamethasone at 4 weekly intervals. Group B consisted of 21 patients with airborne contact dermatitis who received oral daily prednisolone therapy. All the patients had a dual X-ray absorptiometry scan at baseline, and at 3 and 6 months of follow-up. The results were analyzed as changes in bone mineral density. There was loss of bone mineral density at lumbar spine and the head of radius in both the groups. At the lumbar spine, Group B showed more reduction in bone mineral density at 3 months whereas in Group A it was more at the head of radius. In patients on oral steroids, the lumbar spine was significantly more affected than the head of radius at both 3 and 6 months of follow-up. However, in patients on intravenous pulse steroids, both the sites were equally affected at 3 and 6 months. In our study, we used different glucocorticoids in the two groups: prednisolone in the oral daily group and dexamethasone in the intravenous pulse steroids group. A similar reduction in bone mineral density in both the groups may have been due to a longer half-life or more bone-directed side effects of dexamethasone as compared to prednisolone. Dermatologists need to be aware of the detrimental effects of high-dose intravenous pulsed glucocorticoids on bone mineral density and assessment of this parameter should be done before the initiation of therapy and also at regular intervals thereafter. During follow up, either the lumbar spine or the head of radius can be used to assess the osteopenic effect of intravenous pulse steroids, whereas the lumbar spine is a better site for this evaluation in patients on oral steroids.

Endokrinní orbitopatie: aktuální pohled klinického endokrinologa

Graves orbitopathy (GO) occurs in 25-50 % cases of Graves disease. Only in 5 % of patients the eye threatening GO is present. About 5-10 % and 10 % cases are present in euthyroid and hypothyroid patients respectively. All patients with GO should be assessed for activity (clinical activity score - CAS) and severity of the disease. Basic preconditions of the treatment are maintenance of euthyroidism, an effort to stop smoking, and referring of patients with moderate to severe and sight threatening GO to specialized thyroid eye centers. The first line treatment includes maintenance of wet eye (lubricants), supplementation of selenium deficiency, intravenous glucocorticoids, radiotherapy and surgery. Cases with moderate to severe GO should be treated with intravenous glucocorticoids in thyroid eye centers, however, the risk/benefit ratio in all cases should be considered. Cases with sight threatening GO should be immediately referred to thyroid eye centers, high-dose intravenous glucocorticoids are administered, and when the clinical response is absent within 2 weeks, surgical orbital decompression is recommended. Other immunosuppressive drugs (cyclosporine, mycophenolate mofetil) or biological therapy (teprotumumab) are not routinely recommended because of lack of evidence obtained by randomized controlled trials.Key words: clinical activity score - dysthyroid optic neuropathy - Graves orbitopathy - intravenous glucocorticoids - mycophenolate mofetil.

Variables Affecting the Long-Term Outcome of Graves Orbitopathy Following High-Dose Intravenous Glucocorticoid Pulse Therapy in Patients not Treated with Orbital Radiotherapy

Intravenous (iv) glucocorticoids (GC) (ivGC) are used for active Graves orbitopathy (GO), but factors affecting GO outcome are poorly understood. We performed a retrospective study to investigate the variables affecting GO after ivGC. We evaluated 83 consecutive GO patients treated with ivGC but not orbital radiotherapy (ORT) and re-examined them after a median of 47 months. The endpoints were the relationships between GO outcome or additional treatments with age, sex, smoking habits, thyroid volume, thyroid treatment, time since thyroid treatment, antithyroid-stimulating hormone receptor antibodies (TRAb), GO duration, GO features, and follow-up time. GO features improved after treatment, resulting in moderate and marked amelioration in ~75% and ~41% of patients respectively. By multivariate analysis, a moderate GO improvement correlated with diplopia at first observation, which was more severe in responders. A marked GO improvement correlated with time between first and last observation and time after thyroid treatment, which were longer in responders. This likely reflected the combination of an early effect of GC and a late, spontaneous improvement of GO, as shown by analyses of GO outcome at various time points. Additional treatments after ivGC correlated by multivariate analysis with eyelid aperture, diplopia and NOSPECS score (NOSPECS stands for no GO signs [N], only eyelid sign [O], soft tissue involvement [S], proptosis [P], extraocular motility restriction [E], corneal involvement [C], and sight loss [S]) at first observation, which were more severe in responders. Our study shows that response to ivGC increases with time, likely reflecting the known tendency of GO to improve spontaneously, and is more pronounced when GO is more severe to begin with, which is associated with more additional treatments. ANOVA = analysis of variance CAS = clinical activity score GC = glucocorticoids GO = Graves orbitopathy 131I = radioactive iodine iv = intravenous ivGC = high-dose intravenous glucocorticoid pulse therapy MMI = methimazole OD = orbital decompression ORT = orbital radiotherapy TRAb = antithyroid-stimulating hormone receptor antibodies.

Statins are not a risk factor for liver damage associated with intravenous glucocorticoid pulse therapy for Graves' orbitopathy.

Acute liver damage (ALD) is associated with high-dose intravenous (iv) glucocorticoid (GC) (ivGC) pulse therapy in ~1% of patients for Graves' orbitopathy (GO). It has been proposed that statins may increase the risk of ALD. Here we investigated the frequency of ALD according to the assumption of statins in a large retrospective cohort study. We studied 1076 consecutive patients with GO given ivGC. ALD was defined as an increase in alanine aminotransferase ≥300U/l. At the time of ivGC, 62 patients were taking statins and 1014 were not. The frequency of ALD has been reported to be 1.2 cases/100,000 statins users and 1300/100,000 in GO patients given ivGC. Thus, the expected frequency of ALD in patients given both statins and ivGC is 1560/100,000. Transferring these data to our series, one would have expected at least 0.96 cases of ALD (~one case), in the 62 patients given both ivGC and statins. However, no cases of ALD were observed in patients given statins, and the previously reported 14 cases of ALD in this series were seen in patients who were not taking statins. The lack of observation of cases of ALD in patients given ivGC and statins is quite reassuring. Although caution should be applied to any patient candidate to ivGC treatment and this should be particularly accurate in patients given statins, our findings somehow justify the use of ivGC in patients under statins, although further studies in larger cohorts are needed to confirm our conclusions.

Therapeutic management of severe relapses in multiple sclerosis.

While not all multiple sclerosis (MS) relapses require treatment, relapses that are bothersome or that impair function should prompt consideration of timely treatment to restore function and minimize disability. Patients with suspected MS relapses should be evaluated to confirm the diagnosis, exclude other causes of neurological dysfunction, and identify potential triggers for relapse or pseudo-relapse, such as urinary tract infections, fever, or metabolic derangements. The diagnosis of an MS relapse is clinical, but MRI may be useful for confirmation and to evaluate for multifocal disease activity. High-dose oral or intravenous glucocorticoids, with or without an oral taper, are first-line therapy for MS relapses. Adrenocorticotropic hormone (ACTH) provides an alternative to glucocorticoid treatment but is currently much more expensive and does not have proven superiority. If the acute neurological deficits remain severe after steroid treatment, and particularly if there is persistent abnormal contrast-enhancement of the symptomatic lesion on repeat MRI, plasma exchange (PLEX) should be considered as an acute rescue therapy for relapse. In exceptional cases, particularly fulminant or tumefactive disease that fails to improve following treatment with steroids and PLEX, cytoxic agents such as cyclophosphamide or B cell-depleting regimens such as rituximab may be considered, although risk must be carefully weighed and the kinetics of such regimens indicate that they probably serve more to accelerate remission of disease activity than as an immediate relapse remedy. A single dose of natalizumab given as acute therapy for MS relapse was shown not to improve clinical outcomes in a randomized controlled trial. Attention to symptom management and promotion of neurorehabilitation are important aspects of MS relapse care. Neuroprotective and neuroreparative therapies remain under investigation, but are likely to become important complementary elements of relapse therapy in the future. Relapses serve as important indicators of MS disease activity. In the context of the emerging treatment paradigm of targeting freedom from evidence of MS disease activity, relapses should prompt consideration of transitioning to a disease-modifying treatment that may offer better efficacy.

Long-term outcome of Graves' orbitopathy following high-dose intravenous glucocorticoids and orbital radiotherapy.

Intravenous (iv) glucocorticoids (GC) (ivGC) and orbital radiotherapy (ORT) are commonly used in active Graves' orbitopathy (GO), with favorable outcomes in up to 80% of patients. However, little is known on the factors that may affect GO outcome in the long term, an issue that we investigated here. We studied retrospectively 96 untreated patients with GO, identified out of 787 consecutive patients who came to our GO Clinic for a follow-up visit between September 2010 and June 2013. After the first observation, patients were treated with ivGC and ORT and were then re-examined after a median period of 55.5 months. The primary end-point was the possible relation between GO outcome and several individual variables. Exophthalmometry, eyelid aperture, CAS, diplopia and visual acuity (the latter only in patients with an initial reduction) improved significantly after treatment. Overall, 67.7% of patients had improved and were considered as responders, whereas the remaining (29.1% stable and 4.5% worsened) were considered as non-responders. Age, smoking, thyroid volume, thyroid treatment, serum anti-TSH receptor autoantibodies and individual GO features at first observation did not affect the outcome of GO, which, in contrast, was affected by gender and by the time elapsed between first and last observation. Thus, the prevalence of responders was higher in females (76.4 vs 48% in males, P = 0.02) and the time elapsed between first and last observation was greater in responders (58 vs 39 months in non-responders, P = 0.02). Whereas the prevalence of responders and non-responders was similar up to 36 months, there was an increase in responders beginning between 37 and 48 months and reaching a peak of ~80% between 61 and 72 months, to plateau thereafter. Given the limitations of retrospective investigations, our study confirms that the combination of GC and ORT is effective in GO and shows that females have greater chances to respond to treatment. The notorious tendency of GO to improve spontaneously with time most likely contributes the long-term outcome of the eye syndrome.

Is high dose intravenous methylprednisolone pulse therapy in patients with Graves' orbitopathy safe?

High dose intravenous glucocorticoid pulse (i.v. GCS) therapy is a proven approach in patients with active, moderate to severe Graves' orbitopathy (GO) and dysthyroid optic neuropathy (DON). In moderate to severe GO, the European Group on Graves' Orbitopathy (EUGOGO) recommends a 12-week course of intravenous methylprednisolone (i.v. MP) pulse therapy with a cumulative dose of 4.5 g. The response rate of i.v. GCS treatment is significantly higher than oral glucocorticoid (oral GCS) therapy and is associated with fewer adverse events. However, a major concern was raised because of reports of fatal side effects which may be associated with this therapy, especially when single and cumulative doses of methylprednisolone (MP) are higher than recommended. The prevalence and severity of adverse effects during treatment have not been fully described. The aim of this review was to summarise the frequency of major adverse effects of i.v. GCS compared to oral GCS and attempt to propose some practical suggestions as to how to monitor and prevent the development of side effects.

What is the best therapeutic approach if the initial glucocorticoids therapy of active Graves’ orbitopathy fails?

Glucocorticoids are the first-line treatment for active moderate-to-severe and sight-threatening Graves’ orbitopathy. Glucocorticoid therapy, by exerting antiinflammatory and immunomodulatory effects, reduces pain, injection and edema of orbital tissues and provides a substantial relief from optic nerve compression. Although efficiency of both oral and intravenous glucocorticoids is proven, the randomized clinical trials revealed that intravenous therapy is more effective and better tolerated. However, 20-40% of patients respond only partially or do not respond to immunosuppressive treatment. The effectiveness of treatment may be improved by proper selection of patients suspected to have beneficial results, i.e. those with a high degree of disease activity, with orbitopathy of recent onset or recent progression. Corticotherapy may cause major side effects which make treatment continuation impossible. Orbital radiotherapy exerts nonspecific antiinflammatory effect and suppresses radiosensitive lymphocytes infiltrating the orbital space. Orbital radiotherapy remains an effective and safe second-line treatment preferably used in association with glucocorticoids. The combined therapy is more effective than either treatment alone. Sight-threatening Graves’ orbitopathy due to compressive optic neuropathy or corneal ulceration requires immediate intervention. High-dose daily intravenous glucocorticoids are the first-line treatment and if the response is absent or poor within 1-2 weeks the orbital decompression should be performed. Corneal breakdown should be additionally treated with topical lubricants, and sometimes, to provide eyelid closure, with blepharorraphy or tarsorraphy. Unsuccessful oral glucocorticoid treatment of active Graves’ orbitopathy should be an indication for orbital radiotherapy, preferably combined with glucocorticoids, or to a 3 month intravenous methylprednisolone course. If intravenous methylprednisolone was the first treatment and the response is not satisfactory, the intravenous course should be repeated combined with orbital radiotherapy. An alternative approach is combination of oral or intravenous glucocorticoids with cyclosporine for 3-6 months. It was demonstrated that the combined treatment of cyclosporine with oral glucocorticoids resulted in substantial improvement and was useful to reduce the dose of glucocorticoids. In steroid unresponsive Graves’ orbitopathy, biological agents as anti-lymphocyte antibody (anti-CD 20, rituximab) and anti-cytokine antibody (anti-TNFα, etanercept) have shown promise. Theoretically somatostatin analogue pasireotide, with a wider than octreotide or lanreotide binding affinity for various somatostatin receptor subtypes could be also a treatment option. As far as the randomized clinical trials are not available, the use of biological agents and somatostatin analogs is experimental. We hope that the future treatment will be based on pathogenic mechanisms of Graves’ orbitopathy. Small molecule “drug like” TSH receptor neutral antagonists were shown to antagonize TSAb activation of TSH receptor on retroorbital preadipocytes and possibly could be used to treat Graves’ orbitopathy. Currently their effects were determined in the model of orbit cells.

High-Dose Intravenous Glucocorticoid Therapy for Graves' Ophthalmopathy: Where Are We Now?

High-Dose Intravenous Glucocorticoid Therapy for Graves' Ophthalmopathy: Where Are We Now?