Omalizumab In The Treatment Of Bullous Pemphigoid

BackgroundBullous pemphigoid(BP)is an autoimmune blistering disease(AIBD),which mainly occurs in the elderly and occasionally occurs in children and young adults.Typical clinical manifestation is erythema and subepidermal blister or bullae,associated with negative Nikolsky sign.Patients felt severe pruritus,most of which were not accompanied by mucosal damage.The main target antigens of BP are BP 180 and BP230.Circulating antibodies,including anti-BP180 and anti-BP230 antibodies,can be detected by enzyme-linked immunoassay(ELISA).The histopathological characteristic of BP is characterized by subepidermal blisters formation,as well as inflammatory cells(mainly eosinophils and a few neutrophils)within the blisters and superfacial upper dermis.The diagnosis of BP requires combination of clinical manifestations,skin histopathology,immunofluorescence and ELISA.The majority of BP patients have elevated serum total IgE levels and/or peripheral eosinophilia(EOS).The traditional systematic treatments of BP mainly relies on glucocorticoids,immunosuppressants,non-specific anti-inflammatory drugs(tetracycline and dapsone,etc.)and intravenous immunoglobulin(IVIG),which inhibit non-specific inflammatory response and autoantibody production.Most patients gain improvements after treatment,while some patients are insensitive/intolerant to traditional treatments.Besides the incidence of adverse reactions in elderly BP patients increases after using long-term of glucocorticoids[1].A number of studies have found that anti-IgE antibodies play an important role in the pathogenesis of BP[2-7].Omalizumab(OMZ)is a medication produced from humanized monoclonal anti-IgE antibodies that binds to FcεRI with high affinity and reduces circulating IgE,blocking the combination of IgE with effector cells such as mast cells and basophils,therefore inhibiting the release of inflammatory messengers and blocking the inflammatory cascade.It has been approved by the Food and Drug Administration(FDA)for chronic urticaria,asthma and other IgE-mediated diseases.Foreign researchers have tried to use omalizumab to treat BP patients who are insensitive/intolerant to traditional treatments,which already achieved impressive therapeutic effects,therefore helping to reduce glucocorticoid dosage and therapeutic side effects.However,reports and analyses relevant to the efficacy and safety of omalizumab in the treatment of BP are scarce.ObjectiveIn order to provide a new clinical option for patients with bullous pemphigoid who are insensitive/intolerant to traditional treatments,a retrospective analysis was conducted to evaluate the efficacy and safety of omalizumab combined with glucocorticoid in the treatment of bullous pemphigoid,MethodsClinical data of 7 patients with BP treated with omalizumab were collected from March 2021 to October 2021 in the Department of Dermatology of Qilu Hospital of Shandong University(all patients were diagnosed with BP by several workup including skin biopsy,immunofluorescence and ELISA and signed informed consent).In addition,related literatures on BP treated with omalizumab were analyzed by Wanfang Database,CNKI,Pubmed database and Baidu Academic search.Patients with clinical data including gender,age,underlying diseases,disease’s duration time,severity,time to disease control,serum total IgE level and peripheral eosinophil count before treatment,systematic medication before and during omalizumab treatment,time to reduce the dosage of glucocorticoid,application methods of omalizumab,therapeutic effects and adverse reaction,etc.IBM SPSS Statistics 26.0 and Graphad Prism 8.0 were used for statistical analysis and plotting.P<0.05 was considered statistically significant.ResultsPart I:Case seriesClinical data of 7 BP patients treated with omalizumab in the Department of Dermatology of Qilu Hospital of Shandong University are as follows:Patient 1:80-year-old male with a history of type 2 diabetes and hypoproteinemia.He presented repeated erythema,blisters and severe pruritus of the whole body for 13 months.The conjunctiva,oral and perineal mucosa were not involved.Systemic treatment of glucocorticoid(the maximum dose of methylprednisolone is 80mg/d),minocycline hydrochloride,nicotinamide,mycophenolate mofetil and methotrexate was performed,but the disease was not completely relieved.One month ago,his skin blisters extended and the disease condition worsened(prednisone 10mg per day combined with methotrexate 7.5mg per week).On physical examination,BPDAI scores were 95(rated as severe).Anti-BP 180 and anti-BP-230 were detected in the patients’ serum by ELISA,respectively over 200IU/ml and at 177.0 IU/ml.Blood routine examination showed EOS count was 0.92x109/L and total serum IgE is 177IU/ml.During the hospitalization,the patient was treated with glucocorticoid(methylprednisolone 40mg/d×7d,dexamethasone 10mg/d×6d),minocyclic(100mg/d×3d),nicotinamide(750mg/d×3d),IVIG(25g/d×5d),and mycophenolate mofetil(1.0g/d×12d)for 12 days,which failed to control the disease.Countercheck EOS count revealed 12.46×109/L.In the presence of high IgE levels and ESO count,omalizumab(subcutaneously injected 300mg every two weeks)was used in combination with methylprednisolone treatment(60mg/d×16d,54mg/d×2d).Clinical efficacy was obtained after 18 days of treatment.On the 35th day of hospitalization(methylprednisolone dose was 36mg/d),the patient went back home and continued omalizumab treatment for 5 times(subcutaneous injection of 300mg every 4 weeks).Besides glucocorticoid dosage was gradually reduced,partial remission of the disease was achieved.However,the patient presented recurrence after omalizumab discontinuation for 2 months.At that time,the dosage of prednisone was 10mg per day.Patient 2:74-year-old male with a history of hypoproteinemia and hepatic dysfunction was admitted to hospital for repeated erythema,blisters,erosion and pruritus of the whole body for 5 months.The conjunctiva,oral and perineal mucosa were not affected.BPDAI score was 64(rated as severe).Laboratory test:anti-BP180 antibody>200IU/mL,anti-BP230 antibody was positive;Blood routine examination showed EOS count of 0.22×109/L and raised IgE was 2890IU/ml.11 days of intravenous treatment with methylprednisolone 40mg/d and IVIG(30g/d×5d)presented no clinical remission.The new serology reveals EOS count was 1.93×109/L and total serum IgE level was 14700IU/ml.Based on the intravenous treatment with methylprednisolone 40mg/d,omalizumab 300mg was administrated subcutaneously.Unfortunately,the disease was failed to be controlled,with no significant clinical efficacy and alleviation of pruritus.Patient 3:53-year-old male with a history of hypoproteinemia and hepatic dysfunction presented to clinic for his erythema and pruritus on bilateral upper limbs for 2 months.The blisters and bullae appeared and spread all over the body for more than 20 days.Conjunctiva,oral and perineal mucosa were not involved.BPDAI score was 58(rated as severe).Laboratory tests showed anti-BP180 antibody was over 200IU/mL and anti-BP230 antibody was negative.Blood routine examination showed EOS of 0.85×109/L and raised IgE at 553.0IU/ml.During hospitalization,methylprednisolone(40mg/d×2d,80mg/d×9d)combined with IVIG(25g/d×5d)were administered intravenously for 11 days.The disease was poorly controlled and liver function began to be abnormal(alanine aminotransferase(ALT)was 71U/L).After 12 days of treatment,the total serum IgE level elevated to 1580.0IU/mL.Omalizumab 300mg subcutaneously injected was began in combination with methylprednisolone and prednisone,40mg/d and 25mg/d respectively.After 16 days of hospitalization,the new blisters gradually decreased.The patient decided to go home to continue omalizumab treatment for 5 times(SC 300mg every 4 weeks).The number of blisters reduced,with glucocorticoid dosage gradually decreased.While the skin lesions did not disappear significantly,with new blisters still recurred.Finally,the disease could not be controlled.Patient 4:80-year-old female with a history of cerebral infarction and hypertension was admitted to the clinic for skin erythema,blisters on trunk and limbs with pruritus for 40 days.Her conjunctiva,oral and perineal mucosa were not involved.She has been treated with prednisone 15mg/d,minocycline 200mg/d as well as nicotinamide 750mg/d for 1 month,while the clinical efficacy was not impressive.BPDAI was evaluated at 75(rated as severe).Laboratory tests showed anti-BP180 antibody and anti-BP230 antibody were 171.6IU/mL and 68.5 IU/ml respectively;Blood routine examination showed EOS was 1.37×109/L and total serum IgE level was 219.0IU/ml.During the hospitalization,the patients were treated with glucocorticoid(prednisone 20mg/d×ld,dexamethasone 5mg/d×1d,dexamethasone l0mg/d)and nicotinamide 750mg/d for 3 days,the disease failed to be controlled.Omalizumab treatment(SC 300mg)was considered to apply.The disease was controlled 5 days subsequently.She decided to went back home 9 days after hospitalization,with oral prednisone 50mg/d.After 3 months of follow-up,the patient’s condition was stable and the glucocorticoid dosage was gradually reduced to 20mg/d.The disease was partially alleviated.Patient 5:A 26-year-old female with obesity was admitted to hospital due to extensive erythema,blisters with pruritus for 2 years.Conjunctiva,oral and perineal mucosa were not involved.The patient was treated with methylprednisolone(maximum dose 40mg/d),minocycline hydrochloride 100mg/d,IVIG(25g/d×5d),nicotinamide 750mg/d and cyclosporine 300mg/d for 2 years.Methylprednisolone had been discontinued for 2 months,with the lesions recurred 1 month ago.The BPDAI score was 47(rated as mild).Anti-BP 180 antibody showed positive and anti-BP230 antibody presented negative,derived from laboratory test;Blood routine test showed EOS was 0.02×109/L and total serum IgE was 17.1U/ml.During hospitalization,patients were treated with methylprednisolone 40mg/d intravenously for 5 days,but repeated blisters still appeared on the her waist.After 2 days of treatment with Omalizumab(SC 300mg),the disease was controlled.35 days after hospitalization,the dosage of methylprednisolone reduced to 36mg/d.The patient was regularly treated with omalizumab(SC 300mg every 4 weeks)for 3 times at home.After 9 months of followed-up,the disease achieved complete remission,with sustained methylprednisolone at 4mg/d.Patient 6:82-year-old female with a history of cerebral infarction,hypoproteinemia,and hypokalemia.She was admitted to hospital for extensive erythema with pruritus for 6 weeks,associated with skin blisters and bullous on trunk and limbs for 1 week.Conjunctiva,oral and perineal mucosa were not involved.BPDAI was 56(rated as moderate).Laboratory tests showed anti-BP180 antibody and anti-BP230 antibody were over 200IU/mL and 146.6IU/ml respectively;Blood routine test showed EOS was 0.23×10^9/L.Total serum IgE raised to 1410IU/ml.After intravenous treatment with methylprednisolone(40mg/d×2d),there were still many new blisters,with no pruritus alleviation.Omalizumab treatment(300mg subcutaneous injection once)was used for 5 days,the condition was initially controlled.After discharge,the patient continued to receive intravenous methylprednisolone 40mg/d for 1 week,and then stopped glucocorticoids therapy on his own.The patients were followed up for 8 months and the disease was in complete remission.Patient 7:A 65-year-old woman with a history of hypertension was admitted to hospital for skin erythema with pruritus on the whole body for 1 year,with pharyngeal mucosa erosion and skin blisters on the trunk and limbs for 1 month.BPDAI scores were assessed at 42(rated as moderate).Laboratory test showed anti-BP180 antibody was over 200IU/mL and anti-BP230 antibody was negative;Blood routine test showed EOS was 0.4×109/L.Total serum IgE elevated to 264IU/ml.During hospitalization,patients were treated with methylprednisolone 40mg/d,nicotinamide 900mg/d and minocyclic hydrochloride(100mg/d×4d)for 6 days.There were still many new blisters,and the culture outcome of pharyngeal erosion showed Acinetobacter pittii.Omalizumab 300mg was injected subcutaneously once.3 days later,the patient was treated with prednisone 40mg/d.Irregularly omalizumab treatment was applied(300mg subcutaneous injection)after discharge.After 6 months of follow-up,the dosage of prednisone was reduced to 15mg/d.Her pharyngeal erosion had healed,with the disease partially be alleviated.Part Ⅱ:Literature review and clinical characteristics analysis27 BP patients treated with omalizumab(alone or in combination with other drugs)collected from 13 literatures reported around the world between 2019 and February 2022 through database retrieval and 7 BP patients treated in the department of dermatology of Qilu Hospital of Shandong University,total of 34 cases,were included for analysis.1.Gender and age:There were 15 males and 19 females(ratio 1:1.27).The median age was 74.0(64.5,80.3)years.2.History of disease:Among the 34 patients,19 cases had disease’s record.The median history was 6.0(2.0,13.0)months,and the standard deviation was 7.2 months.3.Underlying diseases:Among the 18 patients with underlying diseases,4 patients(22.2%)had one underlying disease,and 14 patients(77.8%)had more than one underlying diseases.There were 7 patients(18.4%)with hypertension,5 patients(13.2%)with osteoporosis/fracture,4 patients(10.5%)with type 2 diabetes,and 3 patients(7.9%)with cerebral infarction or other neurological diseases(ND).4.Disease severity:Using BSA/BPDAI to assess the disease severity.One patient was rated as mild(2.9%),13 patients were moderate(38.2%),15 patients were severe(44.1%),and the severity of disease was unknown in the remaining(14.8%).5.Systematic treatment before applying omalizumab:the average kinds of systematic treatment method of 34 patients before omalizumab treatment was 2.21,and 8 patients(23.5%)had used one kind of treatment;16 patients(47.1%)had been treated by two systematic drugs.5 patients(14.7%)had been treated by 3 kinds of systematic medications.5 patients(14.7%)had been treated with 4 kinds of systematic medications.6.Dosage of systemic glucocorticoid before omalizumab treatment:24 patients(all aged≥40 years)had specific dose of glucocorticoid(according to prednisone dose),the average dose was 55.2mg/d.The maximum dose and minimum dose was 100mg/d and 5mg/d,respectively.The standard deviation was 25.7mg/d.7.Laboratory tests before omalizumab treatment:7.1 Anti-BP180 and anti-BP230 antibody levels:Among the 34 patients,30 had anti-BP180 antibody records,among which 28(93.3%)were positive and 2(6.7%)were negative;The results of anti-BP230 antibody were recorded in 25 cases,of which 15(60.0%)were positive and 10(40.0%)were negative.13 cases were positive for both.7.2 Serum total IgE levels:Serum total IgE levels were recorded in 32 patients,of which 31 patients(96.9%)had higher than normal,with median of 1151(346.5,2440.5)IU/ml.7.3 Peripheral blood EOS counts/ratio:The peripheral blood EOS counts/ratio was recorded in 33 patients,among which 22 cases(66.7%)were higher than normal and 11 cases(33.3%)were within the normal range.8.Application of Omalizumab:8.1 Dosage and interval of omalizumab application:4 patients(11.8%)did not regularly receive omalizumab treatment(times<2 or intermittent application).30 patients(88.2%)were regularly treated with omalizumab:25 patients were treated with 300mg,18 of whom were injected subcutaneously once every 4 weeks;4 patients received 375mg,including 3 patients received subcutaneous injection once every 2 weeks and 1 patient received subcutaneous injection once every 4 weeks.8.2 Treatment duration of Omalizumab:21 patients recorded the treatment duration of omalizumab,among which 16 patients were regularly treated with Omalizumab,and 3 patients(18.8%)were treated with omalizumab for less than 3 months;9 cases(56.3%)were treated for less than 12 months.4 cases(24.9%)were used for more than 12 months.9.Therapeutic effects:9.1 Outcomes:Among 34 patients,25 patients achieved various response(73.5%),including complete response in 18 cases(52.9%)and partial response in 7 cases(20.6%).5 patients relapsed after drug withdrawal(14.7%),with a median recurrence time of 12(8,16)weeks.4 patients(11.8%)experienced no disease control.9.2 Systematic use of glucocorticoids after omalizumab treatment:When applying omalizumab treatment,21 of 25 patients in the remission group had been systematically used glucocorticoids.After treatment,11 patients(52.4%)stopped using systemic glucocorticoids,10 patients achieved complete remission(4 patients received omalizumab maintenance single therapy),and 1 patient achieved partial remission.Glucocorticoid reduction was achieved in 7 patients(33.3%),including complete response in 3 patients and partial response in 4 patients.The median time to first glucocorticoid reduction after omalizumab treatment was 8.0(4.0,20.0)days,and the median dose reduction was 15(7.5,33.5)mg/d.9.3 Time of disease control:Among the 34 patients,12 patients had recorded time of disease control.The duration are listed as follows:7 patients(58.3%)≤7 days,3 patients(25.0%)≤14 days,and 2 patients(16.7%)≤28 days;The median time of disease control was 6(4,14)days.10.Adverse effects:Among the 34 patients,1 patient(3.0%)showed suspected adverse reactions at the injection site,while the rest showed no adverse reactions related to omalizumab injection.11.Correlation between gender,age and therapeutic effects:In disease’s remission group,there were 10 males and 15 females;5 males and 4 females experienced disease recurred/uncontrolled.Fisher’s exact test showed no significant gender difference between the remission group and the recurrence/uncontrolled group(P=0.462).The median age of the complete remission group was 76.0(66.0,81.3)years;Median age in the partial remission group was 80.0(67.0,86.0)years.The median age of the recurrence group was 70.0(59.0,78.0)years and the non-control group was 65.5(54.0,74.0).Using ANOVA,there was no significant difference in age among the four subgroups(P=0.558).12.Correlation between disease severity and curative effect:1 patient with mild BP had complete remission(100.0%);Among 13 moderate BP patients,11 were in remission(84.6%),and 2 were experienced disease relapse/uncontrolled(15.4%).Among the 15 severe BP patients,9 cases(60.0%)were in remission,and 6 cases(40.0%)were suffered relapse/uncontrolled.Fisher’s exact test showed no significant correlation between disease severity and curative effect(P=0.129).13.Correlation between serum total IgE level and curative effect:Median total IgE level in complete response group,partial response group,recurrence group and uncontrolled group were 636.0(365.0,1766.0)IU/mL,864.0(252.8,2212.8)IU/ml,1074.0(199.5,7425.5 IU/ml,3906.0(1791.0,12372.0)IU/ml,respectively.Kruskal-wallis test showed no significant difference among the four groups(P=0.469).14.Correlation between peripheral blood EOS count and efficacy:among 22 patients with elevated EOS,13 cases(59.1%)were in remission after omalizumab treatment,and 9 cases(40.9%)were experienced disease relapsed/uncontrolled.Among the 11 patients of normal count,11 were in remission(100.0%).Fisher’s exact test showed a correlation between peripheral blood EOS and efficacy(P=0.013).15.Correlation between treatment duration and efficacy:in 8 patients with treatment duration≤3 mon ths,6 patients(75.0%)experienced remission and 2 patients suffered disease(25.0%)relapsed/uncontrolled;13 patients were treated for more than 3 months,among which 8(61.5%)were in remission and 5 patients suffered disease(38.5%)relapsed/uncontrolled.Fisher’s exact test showed no statistically significant difference between the two groups(P=0.443).16.Correlation between regular treatment and efficacy:among the 30 patients receiving regular treatment,22 cases(73.3%)achieved remission,and 8 cases(26.7%)relapsed/uncontrollable.Among the 4 patients with irregular treatment,3 patients(75.0%)achieved remission,and 1 patient’s(25.0%)disease relapsed/could not be controlled.Fisher’s exact test showed no statistically significant difference between the two groups(P=0.719).Conclusion1.When treating bullous pemphigoid with omalizumab alone or in combination with other systematicmedication,the remission and recurrence rate was 73.5%and 14.7%respectively.The disease uncontrolled rate was 11.8%.The incidence of adverse reactions was 3.0%.2.Remission rate of mild and moderate patients treated with omalizumab was lower than that of severe patients.3.In the treatment of BP patients who are insensitive/contradictive to traditional systematic treatment,omalizumab can rapidly control the disease progression and help reduce glucocorticoid dosage with no significant side effects.