Steroid-sparing Effect Research Articles

Intravenous Immunoglobulin for Inflammatory Myositis: Experience in a Tertiary Medical Center.

Inflammatory myopathies are treated with glucocorticoids and other immunosuppressive medications. Intravenous immunoglobulin (IVIG) is increasingly used for refractory or severe cases; however, the evidence for their effectiveness is limited. We assessed effectiveness and safety of IVIG when used with other immunomodulatory agents in the treatment of inflammatory myopathies. This study reviewed records of patients diagnosed with dermatomyositis or polymyositis and treated with IVIG, from 2009 through 2016 in 1 tertiary medical center. Mixed-effects general linear regression models were applied to determine effectiveness of treatment on muscle strength, creatinine phosphokinase levels, and steroid dosage. Twenty-three patients with dermatomyositis/polymyositis treated with IVIG were followed up for a mean of 31 (SD, ±25) months. During this period, a significant improvement in muscle strength was demonstrated, with a mean increase of 0.92 Medical Research Council scale points (β = 0.14; confidence interval [CI], 0.136-0.149; p < 0.0001), a significant reduction of creatinine phosphokinase levels and steroid dosage with a mean decrease of 1140 IU/L (β = -0.274; CI, -0.354 to -0.195; p < 0.0001), and 36 mg/d (β = -0.008; CI, -0.011 to -0.006; p < 0.0001), respectively. Overall, remission was observed in 10 patients (43.5%), and partial remission in 6 patients (26%), whereas 1 patient (17%) remained refractory to treatment, and 6 patients (27%) were lost to follow-up. The majority of patients with inflammatory myopathies experienced a clinical and laboratory improvement during IVIG treatment. In addition, a steroid-sparing effect was noticed in most patients. These results encourage the use of IVIG as an alternative treatment option for patients with limited responsiveness to conventional methods.

OP0148 MEPOLIZUMAB FOR EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS (EGPA): A RETROSPECTIVE REAL-WORLD EUROPEAN STUDY ON 142 PATIENTS

Background:Evidence on the efficacy of Mepolizumab (MEPO) in Eosinophilic Granulomatosis with Polyangiitis (EGPA) is scarce [1].Objectives:To assess the efficacy and safety of MEPO in real-life clinical practice.Methods:We retrospectively included patients diagnosed with EGPA and treated with MEPO (100 or 300 mg/month). MEPO efficacy was evaluated in the first 12 months in terms of systemic disease and asthma control. The occurrence of any adverse event (AE) was recorded.Results:142 patients were included (38% males; median age 46.4 (IQR 36.7-54.4); 110 and 32 on MEPO 100 and 300 mg/month, respectively). General, ear-nose-throat, pulmonary, and neurological symptoms significantly decreased during treatment (table 1). MEPO accounted for a significant reduction in the BVAS (figure 1) and for a steroid sparing effect (figure 2). The proportion of patients with asthma attacks decreased by 90% at 12 months compared to t0, and asthma-related emergency accesses dropped from 17.4% to 2.3%. Overall, 21.1% of patients had a non-serious AE.Table 1.Control of clinical symptomsMEPO beginning (t0)3 monthsp-value(t3 vs t0)6 monthsp-value(t6 vs t0)12 monthsp-value(t12 vs t0)N obsN=142N=135N=123N=89General symptoms40 (28.2%)17 (12.6%)&lt;0.00119 (15.5%)&lt;0.00113 (14.6%)0.002Cutaneous manifestations13 (9.2%)6 (4.4%)0.0085 (4.1%)0.0254 (4.5%)0.180ENT manifestations106 (74.7%)52 (38.5%)&lt;0.00144 (35.8%)&lt;0.00129 (32.6%)&lt;0.001Pulmonary manifestations130 (91.6%)59 (43.7%)&lt;0.00139 (31.7%)&lt;0.00128 (31.5%)&lt;0.001Cardiac manifestations6 (4.2%)2 (1.5%)0.0832 (1.6%)0.08300.157Intestinal manifestations10 (7.0%)1 (0.7%)0.0054 (3.3%)0.0593 (3.4%)0.059Renal manifestations5 (3.5%)3 (2.2%)0.41400.0461 (1.1%)0.317Neurological manifestations36 (25.4%)22 (16.3%)0.01218 (14.6%)0.00310 (11.2%)0.035Figure 1.Changes in BVASFigure 2.Steroid treatmentConclusion:MEPO effectively controlled systemic and respiratory EGPA symptoms in a large European cohort, with no major safety concerns.

FRI0506 EFFICACY AND SAFETY OF CANAKINUMAB IN ADULT-ONSET STILL’S DISEASE: A SINGLE-CENTER REAL-LIFE EXPERIENCE

Background:The pro-inflammatory cytokine interleukin (IL)-1 has a central role in the pathogenesis of adult-onset Still’s disease (AOSD), a rare auto-inflammatory condition. Anakinra, has been for years the cornerstone of IL-1-blocking therapy in AOSD. More recently, the monoclonal antibody canakinumab, a new agent blocking IL-1, has become availableObjectives:To describe our real-life experience with CNK in a cohort of AOSD patients from a single Italian CenterMethods:AOSD patients diagnosed according to Yamaguchi’s criteria followed-up at our Autoinflammatory Unit and treated with CNK for at least 3 months were included. Demographic features, disease characteristics, reasons for CNK introduction, concomitant therapies, variation in systemic steroids dose, adverse events, and response to treatment were retrospectively evaluated. Non-parametric tests were used for statistical comparisonResults:13 patients (5 women; median age 49 years, range 21-74), treated with subcutaneous CNK 4 mg/kg 4-weekly, were identified. Median disease duration before CNK introduction was 12 (6-240) months. After CNK introduction, 2 patients were followed-up for 18 months, 3 for 12 months, 6 for 6 months, 2 for 3 months. CNK was introduced as first-line biologic DMARD in 6 patients. The other 7 patients had been already treated with at least one other bDMARD, for a total of 15 treatment courses (7, anakinra, ANK; 4, tocilizumab; 4, TNF-inhibitors), with a median bDMARD therapy duration of 8 (4-178) months. Previous bDMARDs had been interrupted because of inefficacy (8 cases) or adverse events (AE, 7 cases); of the 7 ANK-treated patients, therapy interruption was due to inefficacy in 3 cases. At CNK introduction, 11 patients were on systemic steroid therapy, prednisone (PDN) equivalent dose 15 (5-80) mg, and 10 were concomitantly receiving a conventional DMARD (7, methotrexate; 2, colchicine; 1, cyclosporine-A).Graphic 1summarizes main clinical features at CNK introduction. After CNK start, a striking and rapid clinical response was observed, as demonstrated by a substantial decrease of modified Pouchot score and a normalization of acute phase reactants after only 3 months (see Table 1 for details). CNK showed also a significant steroid-sparing effect: median PDN dose was reduced to 7.5 (2.5-12.5) mg at month 3 and 5 (0-7.5) mg at month 6; PDN was stopped in 3 patients (1 at month 3, 1 at month 6, 1 at month 12) due to optimal disease control. CNK was temporarily held-off in 3 patients (zoster reactivation, 1; prostatitis, 1; mild leukopenia, 1). We observed no case of primary inefficacyTable 1.Disease activity and blood tests at canakinumab introduction and during follow-upDaily prednisone dosemgBaseline(n=13)3 months(n=13)6 months(n=11)12 months(n=5)18 months(n=2)Pouchot score15 (5-80)7.5 (2.5-12.5)5 (0-7.5)5 (0-7.5)2.5VAS pain3 (2-5)1 (0-2)0 (0-1)00Erythrocyte sedimentation ratemm/h7 (2-10)3 (1-8)2 (1-4)1 (1-2)1C-reactive proteinmg/L42 (8-120)21 (2-69)13 (2-55)14 (2-41)11Ferritinng/mL20.8 (3-180)3.1 (0.5-22.5)1.6 (0.5-8.4)1 (0.3-6.3)0.5Hemoglobing/dL379.5 (161-914)282 (82-552)215 (34-464)177 (77-401)19913.1 (9.4-15.7)13.2 (10.7-15.3)13.8 (11.5-15.5)13.9 (11.3-14.3)13.5Figure 1.Graphic 1 Main clinical features at canakinumab introductionConclusion:Our real-life data confirm that CNK is highly effective and safe in AOSD treatment and has significant steroid-sparing effects. CNK showed its efficacy both as first-line therapy and after other bDMARDs failure, also in patients who have previously failed IL-1 inhibition through ANK

FRI0121 STEROID-SPARING EFFECT OF JAK INHIBITORS IN RHEUMATOID ARTHRITIS PATIENTS FOLLOWED UP IN A REAL LIFE SETTING

Background:Glucocorticoids (GCs) are a milestone of Rheumatoid Arthritis (RA) treatment; EULAR recommendations on the management of medium to high dose glucocorticoids remind to evaluate comorbidities and risk factors for adverse events when planning GCs treatment. Tofacitinib and Baricitinib are Janus kinases inhibitors (JAKi) registered for RA treatment. About 60% of patients enrolled in randomized clinical trials with JAKi were co-treated with GCs; however, little is known about tapering and percentage of withdrawal both in clinical trials and real life.Objectives:To evaluate the steroid-sparing effect of JAKi in patients with RA.Methods:We prospectively enrolled consecutive adult patients with RA starting JAKi. At baseline and after 4, 12 and 24 weeks we calculated C-Reactive Protein based Disease Activity score 28 (DAS28CRP). Daily dose of GCs was recorded at each visit as prednisone (PDN)-equivalent dose. Data are expressed as median (IQR). Continuous variables were compared by Mann Whitney test while dichotomous ones by Chi-square test. P values &lt; 0.05 were considered statistically significant.Results:Between January 2018 and January 2020, 108 patients started JAKi: 67 patients Baricitinib, 41 patients Tofacitinib. The analysis was restricted to 64 RA patients (50 female, 14 male) who had at least 6 months of follow-up. Table 1 shows the demographic, clinical and clinimetric characteristics of the cohort. Patients treated with baricitinib and tofacitinib were comparable for age, disease duration, PDN dose and previous number of csDMARDS and bDMARDS; 30 patients (47.6%) were treated with JAKi in monotherapy. At baseline, the median daily PDN dose was 5 (7.25) mg; after 4, 12 and 24 weeks the median daily dose significant decreased to 5 (6.25) mg, 2.5 (5) mg and 0 (5) mg, respectively (p&lt;0.0001). The percentage of patients treated with GC decreased from 81.5% to 63.5% at week 4, and to 48.4% at week 12 and 24. After 4, 12 and 24 weeks we detected a significant reduction of DAS28 (p&lt;0.00001 compared to baseline). A similar percentage of patients who withdrew PDN compared to those who were still on PDN achieved remission after 12 and 24 months. Similarly, the reduction in DAS28 was comparable between the two groups at week 4 [4.8 (4.2) in those who withdrew vs 4.1 (1) in those who did not] at week 12 [4.8(1.6) for both] and at week 24 [3.7 (1.4) in those who withdrew vs 2.3 (0.7) in those who did not].Table 1.Demographic, clinic and clinimetric characteristics of the 64 patientsBaricitinib= 41Tofacitinib=23P valueFemale:male33:817:6P=nsAge, median (IQR), years58 (15)66 (14.5)P=nsDisease duration, median (IQR), months144 (144)150 (120)P=nsN° of previous csDMARDS3 (3)3 (1)P= nsN° of previous bDMARDs2 (3)1 (3)P= nsDAS28CRPat baseline4.7 (1.6)4.8 (2)P=nsPDN dose at baseline, median (IQR), mg5 (7.5)5 (5)P=nsPDN dose at 4 weeks, median (IQR), mg5 (7.5)5 (5)P=nsPDN dose at 12 weeks, median (IQR), mg2 (5)2.5 (4.7)P=nsPDN dose at 24 weeks, median (IQR), mg0 (5)2.5 (0)P=nsIQR: interquartile range; DAS28CRP: Disease Activity Score 28 using C-Reactive Protein, csDMARDS: conventional synthetic Disease Modyfing anti-rheumatics drugs, bDMARDS: biotheconological Disease Modifying anti-rheumatics drugs PDN= prednisoneConclusion:The rapid reduction of disease activity determined by JAK inhibitors allows a fast tapering of PDN, as suggested by the last EULAR recommendations for the management of RA.Disclosure of Interests:Ilaria Duca: None declared, Francesca Romana Spinelli Grant/research support from: Pfizer, Speakers bureau: Lilly, BMS, Celgene, Fulvia Ceccarelli: None declared, Cristina Garufi: None declared, Silvia Mancuso: None declared, cristiano alessandri Grant/research support from: Pfizer, Rossana Scrivo: None declared, Roberta Priori: None declared, Valeria Riccieri: None declared, Manuela Di Franco: None declared, fabrizio conti Speakers bureau: BMS, Lilly, Abbvie, Pfizer, Sanofi

An In-Depth Analysis of Our Myositis Cohort Following the Example of the EuroMyositis Registry

Background To describe our myositis cohort in-depth. Methods From January 2006 to December 2018, all newly diagnosed myositis patients were retrospectively enrolled in the study. We performed a subtype reclassification using the 2017 EULAR/ACR criteria, following the example of the EuroMyositis registry. Disease activity and damage were measured by the newest standardized assessment-tools for clinical studies. Comparisons between myositis subgroups were conducted using Fisher’s exact test. Results We enrolled 32 patients (25 were female): six patients with dermatomyositis, six with polymyositis, eleven with overlap myositis, six with antisynthetase syndrome, one with autoimmune necrotizing myopathy, one with juvenile antisynthetase syndrome and one with juvenile dermatomyositis. The overall median follow-up period was 23-months (9-44.75). Interstitial lung disease (ILD) was most frequently seen in patients with antisynthetase syndrome. Patients with overlap myositis were more likely to have polyarthritis mimicking rheumatoid arthritis, reduced capillary density in the nail fold capillaroscopy and Raynaud syndrome. Ovarian cancer during the follow-up period occurred in two patients (one with polymyositis and one with dermatomyositis). Myositis-related death was reported in two patients: acute respiratory failure in autoimmune necrotizing myopathy and dysphagia-related complications in polymyositis. Cyclophosphamide, methotrexate and rituximab demonstrated a significant steroid-sparing effect. In 22 of 32 patients, the myositis subgroup classifications made on the basis of our opinion and the new EULAR/ACR classification criteria were different, showing strong disagreement, especially in the subtype polymyositis. Conclusion Our analysis highlights the heterogeneity in myositis subgroups and shows the steroid-sparing effect of cyclophosphamide, methotrexate and rituximab.

Long-term treatment with tocilizumab in giant cell arteritis: efficacy and safety in a monocentric cohort of patients.

ObjectiveThe efficacy of tocilizumab (TCZ) in GCA is supported by two randomized controlled studies, in which TCZ allowed remission to be achieved after 52 weeks of treatment. However, after discontinuation of treatment, half of the patients relapsed. The aim of this study was to analyse the efficacy and safety of long-term treatment with TCZ and the role of fluorodeoxyglucose (FDG)-PET/CT scanning in the follow-up of these patients.MethodsWe collected the clinical data of a monocentric cohort of GCA patients retrospectively.ResultsThirty-two patients were treated with TCZ [25 males and 7 females; age = 74 (59–81) years]. Most of them achieved and maintained clinical remission (1 month: 69%; 3 months: 91%; 6 months: 96%; 12 months: 100%), with serological and FDG-PET/CT scan improvement and a reduction of concomitant glucocorticoid therapy. Nineteen patients were treated for >52 weeks, and in 13 of them a dose tapering was performed, whereas in 2 cases TCZ was suspended for disease remission. Only two patients relapsed: one during TCZ tapering and one after TCZ discontinuation. Ten cases of mild infections and a case of urinary sepsis were reported; in patients treated for >1 year there was no increase in the incidence of side effects compared with patients treated for <12 months.ConclusionIn our cohort of patients, we confirmed the efficacy of TCZ in the induction and maintenance of remission of GCA, demonstrating an important steroid-sparing effect and a good safety profile. Long-term treatment seems to prevent relapse of the disease, suggesting that TCZ treatment can be continued for >52 weeks with efficacy and safety.

Long-term Safety and Effectiveness of Tacrolimus in Patients With Lupus Nephritis: 5-year Interim Postmarketing Surveillance Study in Japan (TRUST).

To assess the long-term safety and effectiveness of tacrolimus for treating lupus nephritis (LN) in the real-world clinical setting. This is an ongoing, open-label, noncomparative, observational, postmarketing surveillance study conducted across 275 sites in Japan. Registered patients with LN were followed for 10 years. Here we report data relating to 5 years of tacrolimus maintenance therapy at the interim data cutoff in August 2016. Of 1395 registered patients, 1355 received tacrolimus maintenance therapy for LN and provided safety data. The most common serious adverse drug reactions (ADR) included pneumonia (1.1%), herpes zoster (1.0%), cellulitis (1.0%), and diabetes mellitus (1.0%). ADR occurred mainly within the first 28 weeks of tacrolimus treatment, and no marked increase was observed during the follow-up period. Subgroup analyses suggested that risk factors for commonly observed ADR associated with tacrolimus included inpatient management, LN disease severity, increasing age, abnormal renal or hepatic function, and comorbid or previous disease. The cumulative rate of progression to renal failure (based on the attending physician's assessment) was 0.8% at Year 1 and 6.6% at Year 5. Cumulative relapse rates were 7.8% and 30.6%, respectively. Urine protein:creatinine ratio, serum anti-dsDNA antibody levels, complement C3 levels, and steroid-sparing effects were all significantly improved from 4 weeks after tacrolimus treatment initiation (P < 0.001) and were sustained over 5 years. Long-term tacrolimus maintenance treatment over 5 years in the real-world clinical setting was well tolerated and effective in a large population of patients with LN (www.ClinicalTrials.gov: NCT01410747).

Corticosteroid reduction by addition of cetirizine and montelukast in biopsy-proven minimal-change nephrotic syndrome concomitant with allergic disorders

Recent reports suggest helper T-cell abnormalities in minimal-change nephrotic syndrome (MCNS), which often complicate allergic disorders that show a similar helper T-cell profile with Th2/Th17 predominance. However, the effect of anti-allergy therapy on MCNS remains unknown. This retrospective study included 51 patients with biopsy-proven MCNS recruited between November 2012 and October 2015, with follow-up through November 2017. We analyzed relapse and temporal daily corticosteroid dose with and without co-administration of histamine H1 receptor antagonist, cetirizine, and cysteinyl-leukotriene receptor antagonist, montelukast, as well as between baseline and after follow-up. Thirteen patients were treated with cetirizine and montelukast in addition to conventional therapy, whereas 38 patients were treated by conventional therapy only, consisting of corticosteroids and immunosuppressants. To adjust for baseline clinical characteristics, a 1:1 propensity score–matched model was applied. The clinical characteristics of the two groups after matching were similar at baseline. The treatment group showed a significant reduction in the lowest daily dose of oral prednisolone throughout the entire treatment course after the study compared to that of baseline (p < 0.025), which was not observed in the control group (p = 0.37), and showed significantly higher percentage of patients establishing corticosteroid-free state for the first time throughout the entire treatment course by addition of cetirizine and montelukast compared to the control group (p < 0.025). The study shows, for the first time, the steroid sparing effect of cetirizine and montelukast in addition to conventional treatment in MCNS patients with concomitant allergies.

Use of monoclonal antibodies for allergic bronchopulmonary aspergillosis in patients with asthma and cystic fibrosis: literature review.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction (HR) mediated by antigens to Aspergillus fumigatus. It is estimated that 2–15% of patients with cystic fibrosis (CF) and between 1% and 5% of asthmatics develop ABPA, affecting approximately 4.8 million people worldwide. The goals of treatment are controlling inflammation, reducing the number of exacerbations and limiting the progression of lung damage. Systemic steroids are therefore used as the mainstay therapy, along with antifungal medications. However, many patients do not respond or develop side effects to treatment. In this scenario, biological drugs such as Omalizumab, Mepolizumab, Benralizumab and Dupilumab have been implemented in clinical practice, even though there is a lack of scientific evidence to support their use. We performed a literature review of the studies carried out which analyzed biologics for the management of ABPA in adult populations with asthma and CF. To our knowledge this is the first literature review that included all biologics. We included a total of 32 studies, all but one were descriptive studies, and the vast majority evaluated the use of Omalizumab. Biologics appeared to have more benefit for patients with ABPA and asthma than CF, specifically at decreasing the frequency of acute exacerbations and by having a steroid-sparing effect. Although a decrease in serum IgE level is considered a measure of therapy success, values may not decline as expected in the context of a significant clinical improvement, highlighting the importance of measuring patient-oriented outcomes. As evidence comes mainly from case series and case reports, randomized controlled trials are needed to evaluate further the safety and efficacy of biologics in ABPA.The reviews of this paper are available via the supplemental material section.

High Relapse Rate in Patients with Polymyalgia Rheumatica despite the Combination of Immunosuppressants and Prednisolone: A Single Center Experience of 89 patients.

Polymyalgia rheumatica (PMR) is an inflammatory disorder in the elderly and is characterized by pain in the shoulders and lower back. Previous studies from western countries have shown that relapse is frequent; however, there are only a few reports on the relapse rate in Japan. Here we examined the relapse rate, and sought to identify factors that predict recurrence in patients with PMR. Of 110 patients who fulfilled the Bird's criteria for PMR between May 2011 and June 2019, 21 patients were excluded, and the remaining 89 patients were followed up until July 2019. Relapse was defined when clinical symptoms were exacerbated and serum C-reactive protein level increased. The relapse-free survival curves were plotted using the Kaplan-Meier method, and log-rank test was used for statistical analysis. The mean age of the 89 patients (50 males and 39 females) was 71.8 years. The mean dose of initial prednisolone (PSL) was 11.8 mg/day. The 1-, 3-, and 5-year relapse-free survival rates were 81.6%, 58.0%, and 52.3% (N = 59, 21, and 7), respectively. In patients who experienced recurrence, the 1- and 3-year second relapse-free survival rates were 58.3% and 27.3% (N = 18 and 3), respectively. Immunosuppressants, such as methotrexate and tacrolimus, were added to PSL in 19 of 30 patients who experienced relapse at the discretion of the attending physicians; however, none of the immunosuppressants worked for preventing second relapses and had steroid-sparing effects. These results indicate that effective immunosuppressants are required to suppress relapse in the treatment of PMR.

Steroid-sparing effect of omalizumab in stage IV (corticosteroid dependent) allergic bronchopulmonary aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) consists of five stages ranging from the acute stage (pulmonary infiltrate, eosinophilia, and increased total Immunoglobulin-E [IgE]) to pulmonary fibrosis. Our patients were diagnosed as Stage IV (corticosteroid dependent) ABPA, in which treatment with systemic corticosteroids cannot be discontinued as symptoms worsen after discontinuation of oral corticosteroids. Omalizumab is a humanized recombinant, monoclonal antibody that selectively binds to IgE to inhibit the immune response to an allergen. It forms immune complexes which not only lower the level of free IgE antibody, but also serve as an allergen buffer, even in cases of markedly high serum IgE >1000 IU/ml in ABPA. In this article, we report three cases of (Stage IV) corticosteroid-dependent ABPA with poor clinical response even after effective treatment with antifungal therapy and courses of corticosteroids (>3 exacerbations/year). After the start of injection omalizumab, the three patients have experienced significant and sustained clinical improvement and improved quality of life with low-dose prednisolone 5 mg every alternate day. The dose of systemic corticosteroids was reduced by 50% in the 1st year and by 70% in the 2nd year although lung function failed to improve.

A Comparison of Azathioprine and Mycophenolate Mofetil as Adjuvant Drugs in Patients with Pemphigus: A Retrospective Cohort Study.

IntroductionAzathioprine (AZA) and mycophenolate mofetil (MMF) are both first-line steroid-sparing agents used for the treatment of pemphigus in combination with a corticosteroid, but few studies to date have directly compared these two combination treatment modalities. The aim of this study was to compare the efficacy and safety of each of these agents as adjuvant therapy with the corticosteroid prednisolone for the treatment of pemphigus, using standardized outcome parameters.MethodsThis was a retrospective study of patients with pemphigus who received corticosteroid therapy in combination with either AZA or MMF at the Autoimmune Blistering Skin Diseases Clinic of Ramathibodi Hospital (Bangkok) between January 2007 and July 2017. The treatment response was evaluated using early [end of the consolidation phase (ECP)] and late endpoints [complete remission (CR) on therapy, CR off therapy and immunological remission]. Cumulative steroid use, relapse rate and adverse events in each treatment group were also compared.ResultsOf the 62 patients with pemphigus included in the study, 37 were treated with prednisolone plus AZA as adjuvant (AZA group) and 25 patients were treated with prednisolone plus MMF as adjuvant (MMF group). The majority of patients in both treatment groups reached the ECP (AZA group 88.2%; MMF group 71.4%; between-group difference not statistically significant at p = 0.156); the median time required to achieve this early endpoint was also comparable (p = 0.362). A high percentage of patients in both the AZA and MMF groups attained CR on therapy (AZA 73%; MMF 72%). The total number of patients who achieved CR on and off therapy were comparable in the two groups (p = 0.933 and p = 0.690, respectively). However, the median time for patients to achieve CR on therapy was significantly shorter for those on MMF than for those on AZA (7.3 vs. 12.5 months; p = 0.019), and the cumulative steroid dose required for patients to achieve CR both on and off therapy was significantly lower in the MMF group than in the AZA group (p = 0.007 and p = 0.043, respectively).ConclusionWhile corticosteroid in combination with either AZA or MMF is an effective therapeutic regimen for the treatment of pemphigus, MMF demonstrates a shorter time to achieve CR on therapy and has a significantly higher steroid-sparing effect.

Rituximab is an effective treatment in patients with pemphigus vulgaris and demonstrates a steroid-sparing effect.

SummaryBackgroundCorticosteroids (CS) with or without adjuvant immunosuppressant agents are standard treatment for pemphigus vulgaris (PV). The efficacy of adjuvant therapies in minimizing steroid‐related adverse events (AEs) is unproven.ObjectivesTo utilize data collected in a French investigator‐initiated, phase III, open‐label, randomized controlled trial to demonstrate the efficacy and safety of rituximab and seek approval for its use in PV.MethodsThis was an independently conducted post hoc analysis of the moderate‐to‐severe PV subset enrolled in the Ritux 3 study. Patients were randomized to rituximab plus 0·5 or 1·0 mg kg−1 per day prednisone tapered over 3 or 6 months, or 1·0 or 1·5 mg kg−1 per day prednisone alone tapered over 12 or 18 months, respectively (according to disease severity). The primary end point was complete remission at month 24 without CS (CRoff) for ≥ 2 months, and 24‐month efficacy and safety results were also reported.ResultsAt month 24, 34 of 38 patients (90%) on rituximab plus prednisone achieved CRoff ≥ 2 months vs. 10 of 36 patients (28%) on prednisone alone. Median total cumulative prednisone dose was 5800 mg in the rituximab plus prednisone arm vs. 20 520 mg for prednisone alone. Eight of 36 patients (22%) who received prednisone alone withdrew from treatment owing to AEs; one rituximab‐plus‐prednisone patient withdrew due to pregnancy. Overall, 24 of 36 patients (67%) on prednisone alone experienced a grade 3/4 CS‐related AE vs. 13 of 38 patients (34%) on rituximab plus prednisone.ConclusionsIn patients with moderate‐to‐severe PV, rituximab plus short‐term prednisone was more effective than prednisone alone. Patients treated with rituximab had less CS exposure and were less likely to experience severe or life‐threatening CS‐related AEs. What's already known about this topic? Pemphigus vulgaris (PV) is the most common type of pemphigus.Corticosteroids, a standard first‐line treatment for PV, have significant side‐effects.Although their effects are unproven, adjuvant corticosteroid‐sparing agents are routinely used to minimize steroid exposure and corticosteroid‐related side‐effects.There is evidence that the anti‐CD20 antibody rituximab is effective in the treatment of patients with severe recalcitrant pemphigus and in patients with newly diagnosed pemphigus. What does this study add? This study provides a more detailed analysis of patients with PV enrolled in an investigator‐initiated trial.Rituximab plus prednisone had a steroid‐sparing effect and more patients achieved complete remission off prednisone.Fewer patients experienced grade 3 or grade 4 steroid‐related adverse events than those on prednisone alone.This collaboration between academia and industry, utilizing independent post hoc analyses, led to regulatory authority approvals of rituximab in moderate‐to‐severe PV.

The effect of dupilumab on lung function parameters in patients with oral corticosteroid-dependent severe asthma

BackgroundIn Phase 3 LIBERTY ASTHMA VENTURE (NCT02528214), add-on dupilumab reduced oral corticosteroid (OCS) use while reducing severe exacerbations and improving pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV1) in OCS-dependent severe asthma patients. ObjectiveThis post hoc study evaluated dupilumab's efficacy based on several lung function parameters for the overall population and subgroups defined by baseline biomarkers. MethodsLung function parameters were pre- and post-BD FEV1, pre-BD forced vital capacity (FVC), FEV1/FVC, and forced expiratory flow 25–75% (FEF25–75%). Dupilumab's steroid-sparing efficacy according to FEV1 improvement (≥ 200 mL vs < 200 mL) or in patients with 0 exacerbations was also assessed. ResultsAt Week 24 in the overall population, pre- and post-BD FEV1 had improved by 0.22 L (95% CI 0.09–0.34; p = 0.0007) and 0.19 L (95% CI 0.08–0.30; p = 0.0009) vs placebo, respectively; FVC by 0.27 L (95% CI 0.13–0.41; p = 0.0003); FEV1/FVC by 1.90% (95% CI -0.26–4.07; p = 0.08); and FEF25–75% by 0.15 L/s (95% CI 0.02–0.28; p = 0.02). Improvements were early and generally sustained over 24-weeks’ treatment. Improvements were observed regardless of baseline eosinophils or FeNO and were generally greatest in patients with eosinophils ≥ 300 cells/μL. Significant steroid-sparing effects were observed with dupilumab irrespective of FEV1 improvement, and in exacerbation-free patients. ConclusionsDupilumab rapidly improved various lung function measures regardless of baseline biomarkers in OCS-dependent severe asthma patients. It showed steroid-sparing effects regardless of FEV1 improvement, and in exacerbation-free patients. This population appears to be highly skewed toward type 2 inflammation.

Efficacy of Methoxsalen Sterile Solution in Conjunction with the Therakos® Cellex® Photopheresis System in Pediatric Patients with Steroid-Refractory Acute GvHD: Interim Analysis

Background: Steroid-refractory acute graft-versus-host disease (SR-aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant in pediatric patients. Second-line therapies cause further immunosuppression, leaving patients vulnerable to life-threatening infections. Extracorporeal photopheresis (ECP) with methoxsalen (Uvadex®) sterile solution, in which apheresed leukocytes are photosensitized, exposed to ultraviolet A radiation ex vivo, and reinfused, is used to treat aGvHD because it has a low risk of infection, unlike systemic immunosuppressants. Safe use of ECP in children is not yet established. Aims: To report interim 4-week data from a 12-week phase 3 study evaluating the efficacy and safety of ECP using the photosensitizing agent methoxsalen with the Therakos® Cellex® Photopheresis System (Cellex; Mallinckrodt Pharmaceuticals, Bedminster, NJ) in pediatric/young adult patients with SR-aGvHD (NCT02524847). Methods: In this single-arm, open-label study, patients (aged 1-21 years; SR-aGvHD International Bone Marrow Transplant Registry [IBMTR] grade B-D) received ECP 3 times/wk for 4 weeks, followed by 2 times/wk for 8 weeks. Steroids were tapered according to physician discretion if SR-aGvHD responded to ECP. The primary endpoint was proportion of patients with an overall response (OR), defined using the Modified IBMTR Severity Index as complete response (CR; complete resolution of aGvHD in all evaluable organs, without next-line systemic treatment) or partial response (PR; improvement of 1 stage in ≥1 aGvHD target organ without progression in others or addition of next-line systemic treatment), after 4 weeks. The primary endpoint was considered significant if P&lt;0.005 for CR+PR vs the null hypothesis (10% response rate), which corresponded to CR+PR &gt;48%. Secondary outcome measures included safety, duration of response, steroid-sparing effect, and organ-specific response. Results: Of 25 patients enrolled, 25 were evaluable for safety (patients who received ≥1 ECP treatment) and 23 were evaluable for efficacy. Patients' mean age was 9.2 years, 44% were female, mean body mass index was 18.3 kg/m2, and the majority (n=18) had Grade 3 aGvHD. Twelve patients (48%) completed all study visits; 5 withdrew early (2 deaths, 1 CR; 3 withdrew due to inadequate efficacy, 2 of whom started second-line therapy, and 3 no longer required treatment) A median of 27 ECP treatments were administered (range 3-28). OR was 61% (14/23 evaluable patients); there were 3 CRs (13%) and 11 PRs (48%; P&lt;0.00001 vs null hypothesis; 95% CI: 36.6, 77.9). OR based on initial organ involvement and overall severity is in the Table. Of the 14 patients who responded by 4 weeks, 9 (64%) and 8 (57%) maintained response at 8 and 12 weeks, respectively. Time to disease progression was a median of 89 days (95% CI: 44.0, 104.0) after enrollment. Median duration of first response was 22.0 days (95% CI: 8.0, 49.0). Among 22 patients evaluable for steroid dose, 9 (41%) had ≥50% reduction in dose by week 4. 103 AEs (11 serious), including 2 deaths (cerebral aspergillosis; disease progression leading to respiratory failure), occurred in 19 patients. Of these, 99 (96.1%), including 2 on-study deaths, were considered unrelated to study treatment, and 4 (nausea, hypocalcemia, hypertension, anemia) possibly related. Conclusions: After 4 weeks of ECP using methoxsalen sterile solution and the Therakos Cellex Photopheresis System, the OR rate was 61%. These encouraging data warrant further investigation in pediatric/young adult patients with SR-aGvHD. Disclosures Kitko: Mallinckrodt: Honoraria; Novartis: Consultancy, Honoraria. Boodée:Mallinckrodt Pharmaceuticals: Employment. OffLabel Disclosure: UVADEXÃ'® (methoxsalen) Sterile Solution is indicated for extracorporeal administration with the THERAKOSÃ'® UVAR XTSÃ'® or THERAKOSÃ'® CELLEXÃ'® Photopheresis System in the palliative treatment of the skin manifestations of Cutaneous T-Cell Lymphoma (CTCL) that is unresponsive to other forms of treatment. Extracorporeal photopheresis (ECP) with methoxsalen (UvadexÃ'®) sterile solution is used to treat acute graft-versus-host disease (aGvHD), but there are few clinical trials in pediatric patients. This abstract reports on the interim results of a phase 3 clinical trial of ECP with methoxsalen used with the TherakosÃ'® CellexÃ'® Photopheresis System in pediatric/young adult patients with steroid refractory aGvHD.

Efficacy, Safety and Steroid-sparing Effect of Topical Cyclosporine A 0.05% for Vernal Keratoconjunctivitis in Indian Children

PurposeTo evaluate the efficacy, safety, and steroid-sparing effect of topical cyclosporine A (Cs A) 0.05% in patients with moderate to severe steroid dependent vernal keratoconjunctivitis (VKC).MethodsA prospective, comparative, placebo controlled study was carried out on 68 VKC patients, with 34 patients treated with topical Cs A 0.05% and the remaining 34 with topical carboxymethyl cellulose 0.5% (placebo). Both groups also received topical loteprednol etabonate 0.5%. Symptom (itching, photophobia, tearing, and discharge) score, sign (tarsal and limbal papillae, corneal involvement, and conjunctival hyperemia) score, and drug score (steroid drop usage/day/eye) were recorded at baseline and each follow-up visit. The intraocular pressure (IOP) measurement and evaluation of any ocular side effects were carried out.ResultsSignificant reduction in symptom score and sign score was seen in both groups. Cs A group significantly showed more reduction in symptom (P 0.0001 in all follow-up visits) and sign (P 0.0001 in all follow-up visits) scores compared to the placebo group. At day 7, mean steroid usage reduced from 4 to 3.44 0.5 and 3.79 0.4 in Cs A and placebo groups, respectively (P 0.0001). Steroid drops completely stopped in 21 patients at day 60 in the Cs A group compared to none in the placebo group. No significant rise in IOP or any side effects were noted in either group.ConclusionTopical Cs A 0.05% is effective and safe in patients with moderate to severe VKC with good steroid-sparing effect.

Mepolizumab for severe eosinophilic asthma: a real-world snapshot on clinical markers and timing of response

ABSTRACTBackground: Few studies have provided real-world evidence of mepolizumab efficacy and safety. We aimed to evaluate mepolizumab for severe eosinophilic asthma in daily clinical practice.Research design and methods: Patients included in the RINOVA (Interdisciplinary Network for the management of severe asthma in Veneto region, Italy) database were investigated. Blood eosinophil count, forced expiratory volume in 1 second, % of predicted (FEV1%), fractional exhaled nitric oxide (FeNO), asthma control test (ACT), oral steroid (OCS) intake, and exacerbation rate were evaluated during mepolizumab treatment.Results: 69 patients were enrolled (mean age: 55.1 years; 60.9% females). A significant improvement was detected at one month with respect to blood eosinophils (median level at baseline: 710/μl; −620/μl, p < 0,001), FEV1% (median value at baseline 87; range: 79–101; +4, p = 0.001) and ACT (median value at baseline 18; range: 14–20.5;+4, <0.001). A significant reduction of FeNO was observed six months after the treatment start, when the exacerbation rate and the mean OCS dose significantly decreased (respectively: Δ reduction −3; p < 0.001 and −5 mg; p < 0.001).Conclusions: Our study provides real-world evidence of mepolizumab safety and confirms its dramatic steroid sparing effect. The greatest clinical change (ACT and FEV1) was observed within the first month.

Oral steroid-sparing effect of high-dose inhaled corticosteroids in asthma.

The proportion of the efficacy of high-dose inhaled corticosteroids (ICS) in oral corticosteroid-dependent asthma that is due to systemic effects is uncertain. This study aimed to estimate the ICS dose-response relationship for oral corticosteroid-sparing effects in oral corticosteroid-dependent asthma, and to determine the proportion of oral corticosteroid-sparing effects due to their systemic effects, based on the comparative dose-response relationship of ICS versus oral corticosteroids on adrenal suppression. Systematic review and meta-analysis of randomised controlled trials reporting oral corticosteroid-sparing effects of high-dose ICS in oral corticosteroid-dependent asthma. In addition, reports of oral corticosteroid to ICS dose-equivalence in terms of adrenal suppression were retrieved. The primary outcome was the proportion of the oral corticosteroid-sparing effect of ICS that could be attributed to systemic absorption, per 1000 µg increase of ICS, expressed as a ratio. This ratio estimates the oral corticosteroid sparing effect of ICS due to systemic effects. 11 studies including 1283 participants reporting oral corticosteroid-sparing effects of ICS were identified. The prednisone dose decrease per 1000 µg increase in ICS varied from 2.1 mg to 4.9 mg, depending on the type of ICS. The ratio of the prednisone-sparing effect due to the systemic effects per 1000 µg of fluticasone propionate was 1.02 (95% CI 0.68-2.08) and for budesonide was 0.93 (95% CI 0.63-1.89). In patients with oral corticosteroid-dependent asthma, the limited available evidence suggests that the majority of the oral corticosteroid-sparing effect of high-dose ICS is likely to be due to systemic effects.

40. A case of large vessel vasculitis presenting with limb claudication symptoms

IntroductionThis is a case report of extensive large vessel vasculitis which initially presented to the vascular team with limb claudication symptoms and an absent radial pulse. CT angiogram was suggestive of a large and medial vessel arteritis, without a significant elevation in ESR.Case descriptionA 71-year-old gentleman was referred from the vascular team to the rheumatology outpatient clinic. He initially attended orthopaedics and was awaiting shoulder surgery. He reported pain and intermittent colour changes in his left hand and was noted to have an absent radial pulse. CT angiogram was suggestive of a large and medium vessel arteritis such as giant cell arteritis. The CT aorta showed occlusion of the left axillary artery with significant narrowing of the left subclavian. He had a known history of cataracts, mixed frequency hearing loss, cervical spondylosis and previous arthroscopic sub acromial decompression surgery. He had intermittent mild jaw pain for a few months but no other clinical symptoms in keeping with vasculitis. He had no headache, scalp tenderness or constitutional symptoms. ESR was 41. Temporal artery biopsy was positive. Histology was in keeping with temporal arteritis but there was no giant cells or granulomata seen. CT PET showed increased tracer uptake within the subclavian, axillary and the common carotid arteries bilaterally. There was also slightly increased tracer extending inferiorly to the aortic arch and within the proximal descending thoracic aorta. He was commenced on 60mg prednisolone OD, omeprazole, adcal D3, alendronate, aspirin and cotrimoxazole. A month later, he presented with chest pain and was diagnosed with acute coronary syndrome. He had extensive imaging and there was no evidence of dissection. He had five coronary stents inserted and was commenced on dual anti platelet therapy for one year. He was commenced on tocilizumab as a steroid sparing agent taking into consideration the severity and extent of his disease, the need for dual antiplatelet therapy and increased bleeding risk.DiscussionThis was an interesting case of extensive large vessel vasculitis without a significant inflammatory response. He had extensive disease with both large vessel and cranial involvement. We held off on steroid treatment until he was investigated with CT PET and biopsy as his symptoms were longstanding. He was a high risk candidate for long term steroids given his recent MI and need for dual antiplatelet therapy. We opted for tocilizumab as a steroid sparing agent given the extent and severity of vessel involvement and increased bleeding risk on antiplatelet treatment. Tocilizumab is licensed for relapsing and remitting GCA and has the ability to limit steroid use and reduce the risk of relapse. Tocilizumab was used as an effective steroid sparing agent in this case.Key learning pointsThis case has shown that extensive large vessel involvement can be seen in vasculitis without a significantly inflammatory response. ESR was only 41 in this case despite the extent of vasculitis. Therefore we must keep an open mind when considering a diagnosis of vasculitis as inflammatory markers may be normal. Tocilizumab was used an effective steroid sparing agent and has helped to limit steroid use in the setting of increased bleeding risk. In patients presenting with these clinical findings, we would have a low threshold for requesting temporal artery biopsy. This patient has established damage due to the extensive vessel involvement and it will be difficult to assess whether symptoms are related to damage or disease activity. How do we best assess whether symptoms are related to damage or disease activity? What is the best imaging to monitor disease activity? How best do we manage this patient’s disease in the long term due to the extent of vessel involvement?Conflicts of interestThe authors have declared no conflicts of interest.

Off-Label Use of Topical Calcineurin Inhibitors in Dermatologic Disorders.

Off-label prescribing is a common practice in dermatology, particularly when uncommon dermatologic diseases have limited or no approved treatment options. Topical calcineurin inhibitors are approved for the treatment of eczema, and their anti-inflammatory, immunomodulatory, and steroid-sparing effects make them an attractive therapeutic option for a wide variety of other dermatologic diseases. This review summarizes and qualifies the available evidence supporting the clinical effectiveness of tacrolimus ointment and pimecrolimus cream in non-eczema indications. There is high-quality evidence supporting the effectiveness of topical calcineurin inhibitors in multiple dermatological disorders including vitiligo; psoriasis of the face, folds, and genitals; seborrheic dermatitis; chronic hand dermatitis; contact dermatitis; oral lichen planus; lichen sclerosus; morphea; and cutaneous lupus erythematosus. Lower-quality evidence suggests they may be considered as an option in many other cutaneous disorders.