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Lot number, expiry date and manufacture date are not available.Investigation: these articles may have been previously reported, however it is unclear as those articles were outside of the search window and have been conservatively included to ensure potential mortality signals have been identified.The articles included from the systematic literature review are: barth d, nabavi nouri m, ng e, nwe p, bril v.Comparison of ivig and plex in patients with myasthenia gravis.Neurology.(2011) 76:2017¿23.Doi: 10.1212/wnl.0b013e31821e5505 schneider-gold c, krenzer m, klinker e, mansouri-thalegani b, müllges w, toyka kv, et al.Immunoadsorption versus plasma exchange versus combination for treatment of myasthenic deterioration.Ther adv neurol disord.(2016) 9:297¿303.Doi: 10.1177/1756285616637046 guptill jt, oakley d, kuchibhatla m, guidon ac, hobson-webb ld, massey jm, et al.A retrospective study of complications of therapeutic plasma exchange in myasthenia.Muscle nerve.(2013) 47:170¿6.Doi: 10.1002/mus.23508 el-bawab h, hajjar w, rafay m, bamousa a, khalil a, al-kattan k.Plasmapheresis before thymectomy in myasthenia gravis: routine versus selective protocols.Eur j cardio-thoracic surg.(2009) 35:392¿7.Doi: 10.1016/j.Ejcts.2008.11.006 rock g, sutton dm, freedman j, nair rc.Pentastarch instead of albumin as replacement fluid for therapeutic plasma exchange.J clin apher.(1997) 12:165¿9.Doi: 10.1002/(sici)1098-1101(1997)12:4<165::aid-jca2>3.0.Co;2-8 citation: ipe ts, davis ar and raval js (2021) therapeutic plasma exchange in myasthenia gravis: a systematic literature review and meta-analysis of comparative evidence.Front.Neurol.12:662856.Doi: 10.3389/fneur.2021.662856 since this is a journal that performed a systematic literature search for studies published between 1997 and 2017 to assess the comparative efficacy and safety of tpe against available treatment modalities and/or untreated patients, the disposable sets were not available for return.Since this is a journal that performed a systematic literature search for studies published between 1997 and 2017 to assess the comparative efficacy and safety of tpe against available treatment modalities and/or untreated patients, the lot numbers were not provided; therefore, a disposable lot history search could not be conducted.The systematic literature review was conducted per preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines with two independent database sources, medline (through the pubmed database) and cochrane library (26).A systematic search of both database sources was conducted for studies published between 1997 and 2017 using predefined search terminology focusing on tpe and myasthenia gravis (mg).All eligible papers were reviewed and a total of 64 papers met the final criteria and were included in the literature review.Of these 64 papers, 13 cited one or more specific tpe systems, including 6 that cited the cobe spectra apheresis system and 1 that cited the spectra optia apheresis system (terumo bct, inc., lakewood, co, usa; formerly caridian bct).All efficacy and safety endpoints captured by 36 comparative safety and comparative efficacy papers were qualified as candidates for meta-analysis.The decision to run a meta-analysis on a specific endpoint was based on two criteria: a) there must be at least 3 papers containing data on that endpoint and b) available data on that endpoint across studies must contain a matching comparator treatment and a comparable study background including treatment context, age group, and outcome measures.Based on these criteria, two endpoints qualified for the metaanalysis.Both compare tpe and ivig in acute mg patients, with one analysis focused on response rate and the other mortality rate.Meta-analysis was performed using a random-effects model to account for the fact that the treatment effect may vary due to a variation in patient populations across studies.The outcome of the meta-analysis was reported as risk differences between tpe and ivig along with 95% confidence intervals (95% ci).The model was fit using the dersimonian and laird method with a continuity correction of 0.5 in studies with 0 cell frequencies (30).Bias in meta-analyses was assessed using egger¿s method (31).Cobe spectra and spectra optia apheresis systems as noted, several types of tpe systems are available to perform tpe procedures in mg patients.Although preclinical publications exist, data comparing the clinical efficacy of different tpe systems was not found in published literature.Most comparative papers either use more than one in a single study or do not specify which was used.Among publications included in this review that specified one or more specific tpe systems, the spectra line of systems, cobe spectra and spectra optia apheresis systems were the most commonly cited (5, 51, 62, 64).Comparative studies that exclusively used both cobe spectra and spectra optia apheresis systems include a prospective, randomized trial of tpe vs.Ivig in acute mg (5).In the tpe group, mean qmgs scores were significantly improved at day 14 and this improvement was maintained through day 28 (p < 0.0001).The majority of tpe patients responded to treatment according to two separate scales 6, but no significant difference was observed in response rate to tpe vs.Ivig on either scale (p = 0.5 to 0.74).Although mean values of qmgs improvement were greater at all time points for tpe compared to ivig, none of the differences were statistically significant (p = 0.07 to 0.13).A retrospective analysis from an institution solely using the cobe spectra apheresis system for tpe found that patients receiving pre-operative tpe using the cobe spectra apheresis system saw improvements following thymectomy compared to those who did not receive a pre-operative tpe (64).Another retrospective analysis, which exclusively used the cobe spectra apheresis system, found that peripheral venous access is associated with shorter hospitalizations compared to central venous access among acute mg patients treated via tpe (62).Lastly, a retrospective analysis comparing tpe vs.Immunoadsorption in acute mg was published by an institution that utilized cobe spectra apheresis system as one of its two tpe systems (as104 from fresenius kabi, bad homburg, germany also used).Findings in the tpe group included a statistically significant improvement in qmgs from baseline to time of discharge (p < 0.0001) (51).However, there was no statistically significant difference in efficacy between the tpe and immunoadsorption groups.Tpe safety mortality no significant increase in mortality risk has been reported for tpe compared to other mg treatment modalities, including ivig.In the pre-thymectomy context, the use of tpe has not been shown to significantly affect mortality compared to untreated patients.In myasthenic crisis, tpe with corticosteroid treatment is associated with significantly lower mortality than treatment with corticosteroids alone.This report provides a complete summary of tpe in mg studies with comparative all-cause mortality data.Tpe vs.No tpe most published studies that compare tpe to an untreated group are within the peri-operative context.In a retrospective analysis of patients receiving (n = 10) or not receiving (n = 9) pre-thymectomy tpe, no deaths were reported among either patient group through 1 year of follow-up (55).Another retrospective analysis compared two pre-thymectomy protocols: a universal protocol in which all patients underwent tpe (n = 74) and a selective protocol in which only ¿high risk¿ patients underwent tpe (n = 90).No deaths were reported under either protocol during hospitalization (64).A third retrospective study, comparing patients receiving (n = 33) or not receiving (n = 53) pre-thymectomy tpe, reported 1 death during hospitalization in each group and no statistically significant difference between the two options (p = 1.00) (56).One very small prospective study reported outcomes for myasthenic crisis patients treated with intravenous methylprednisone (mp) with or without tpe (54).During hospitalization, mortality was significantly higher in patients treated only with mp compared to those who received both mp and tpe (100% mortality, n = 3 vs.0% mortality, n = 4; p = 0.03).The authors note that although all patients were mechanically ventilated, some patients were not treated in the icu due to limited resources.Another, older (1970¿1995) retrospective analysis reported high mortality rates among myasthenic crisis patients treated with or without tpe in a background of pyridostigmine ± prednisolone, but there was no significant difference between the +tpe and -tpe groups (19 vs.10%, p = 0.42) (53).Tpe vs.Ivig as with efficacy, studies of tpe vs.Ivig represent the greatest volume of comparative tpe mortality data.No statistically significant differences between the two have been reported across treatment contexts.For example, the largest published cohort is a retrospective analysis of the healthcare cost and utilization project-nationwide inpatient sample (hcupnis) administrative database, which reported in-patient mortality rates across all mg diagnoses & treatment contexts (1).Although the unadjusted mortality rate was higher in tpe than in ivig (2.6 and 0.6%), the adjusted odds ratio of 2.6 was not found to be statistically significant (p = 0.21).To provide greater strength of evidence within a single treatment context, a meta-analysis of tpe vs.Ivig all-cause mortality in acute mg was performed (table 6).Data from 7 studies were determined to be sufficiently comparable for inclusion in the analysis (see table 7 for study design and demographic summary).Chronic, maintenance studies (25, 45) and mixed cohorts (1)7 were excluded.Mortality risk difference (tpe mortality % minus ivig mortality %), ranged from-5.8% to +5.1%.The pooled estimate based on a random effects model was a +1.5% mortality risk difference (higher risk in tpe) but was not statistically significant (p = 0.264).Egger¿s test did not indicate bias (p = 0.065), but the small number of studies used limits the power of this assessment (31).Thus, even when aggregating data from all published comparisons, there is insufficient evidence to conclude that tpe and ivig have different all-cause mortality rates in acute mg.Mortality data has also been published in the chronic/maintenance setting, though the number of published comparisons of tpe vs.Ivig is far fewer than in acute mg.In one retrospective analysis, 27 juvenile mg patients were treated with tpe or ivig every other week, with tapering if possible (25).Over a median 1-year follow-up, no deaths were reported in either group.Lastly, in a prospective controlled crossover trial, 12 stable, chronic mg patients were treated with a course of tpe or ivig (45).Through 16 weeks of follow-up, no deaths were reported in either group.Optimizing tpe a few studies have also looked at the effects of procedural factors on mortality in mg patients treated with tpe.In a retrospective analysis of the hcupnis administrative database, inpatient mortality was reported for patients receiving early tpe (0¿2 days from admission) or delayed tpe (>2 days from admission) under any mg treatment context (63).All-cause mortality was significantly higher in patients who received delayed vs.Early tpe (6.6% n = 183 vs.1.2% n = 870, p < 0.0001: adjusted odds ratio 1.86, p < 0.0001).A retrospective study of the impact of access route on tpe complications in mg compared mortality for peripheral vs.Central venous access (62).Across a mix of treatment contexts, no deaths were reported in patients receiving tpe via peripheral venous access (n = 100).Two deaths occurred among patients receiving tpe via central access (n = 34), but this difference did not reach statistical significance (p = 0.07).Cobe spectra and spectra optia apheresis systems as noted above for efficacy, data comparing the mortality associated with different tpe systems was not found in published literature.However, table 7 includes all-cause mortality data from several studies captured in this report that used the spectra systems, cobe spectra and spectra optia apheresis systems, exclusively (5, 62, 64) or as one of two cited systems (51, 69).Across all treatment contexts in the studies using cobe spectra and spectra optia apheresis systems exclusively, 2 deaths were reported among 284 treated patients.Both deaths occurred in patients described as having mg-related immobility and were suspected to have been caused by central venous catheter complications: urosepsis and pulmonary embolism (62).Other adverse events studies which resulted in statistically significant differences between tpe, and any comparator treatment were limited to a handful of publications comparing tpe vs.Ivig.While incidence of certain aes is greater in tpe, there are other aes more frequently seen in ivig.Existing evidence points to peripheral venous access and early treatment as the tpe procedural factors most strongly associated with lower ae rates.A compilation of all vascular, cardiac, infection, and other 8 ae rates from comparative studies, including those for which significant differences were not observed, are shown in tables 8¿ 11, respectively.As seen in tables 8¿11, aes other than those listed here may have had higher rates reported in either tpe or ivig, but the differences were not significant, and sufficiently comparable studies could not be identified for a meta-analysis of >2 studies.Pe vs.Ivig aes with significantly higher rates in tpe included cardiovascular aes, infections, renal failure, and citrate reactions, while ivig showed higher rates of extra-thymic tumor formation, headache, and nausea and vomiting.In a combined analysis of all mg patients (crisis and noncrisis) in a retrospective hcupnis analysis (1), the adjusted odds ratio for any severe complication favored ivig, but did not reach statistical significance (odds ratio ivig/tpe: 0.71, p = 0.07).However, among myasthenic crisis patients treated with tpe or ivig, the rates of cardiac complications, systemic infections, and acute renal failure were all significantly higher among tpe treated patients.Cardiac complications, comprising hypotension, fluid overloading, arrhythmias, myocardial infarction, and cardiac arrest, was the most frequently observed category in both tpe and ivig (22.68 vs.11.83%, p = 0.001).The most significant difference between tpe and ivig was observed in systemic infections, which included bacteremia, sepsis, systemic inflammatory response syndrome, and anaphylaxis (9.45 vs.1.18%, p < 0.0001).Acute renal failure was significantly higher in the tpe cohort (4.73 vs.1.18%, p = 0.038).In contrast, rates for non-crisis mg patients were lower for each category and no statistically significant differences were observed between tpe and ivig (cardiac: 9.50 vs.7.60%, p = 0.55; infection: 1.63 vs.1.17%, p = 1.00; renal failure: 0.27 vs.1.17%, p = 0.16; n = 737 and 171, respectively).A fourth ae category, thrombotic complications, exhibited a higher rate in tpe among crisis patients and a lower rate in tpe among non-crisis patients, though neither was statistically significant (crisis: 3.40 vs.0.59%, p = 0.05; non-crisis: 0.27 vs.0.58%, p = 0.46).A prospective, randomized study comparing tpe (n = 41) and ivig (n = 40) in acute mg found significant differences in the rate of several aes (5, 72).Citrate reaction (14.6 vs.0%, p = 0.03) and vasospasm (19.5 vs.0%, p = 0.0054) were observed specifically in tpe.In contrast, headache (0 vs.20.0%, p = 0.0024) and nausea & vomiting (0 vs.17.5%, p=0.0054) occurred solely in the ivig group.A prospective controlled crossover comparison of tpe vs.Ivig as maintenance therapies similarly reported headache as an ivig-specific adverse event (0 vs.58%, p = 0.0046) (45).Optimizing tpe a few studies have also looked at the effects of procedural factors on specific adverse events, beyond mortality, in mg patients treated with tpe.Significantly better safety outcomes were achieved when tpe was performed soon after hospital admission and via peripheral venous access.A retrospective study compared adverse event rates in tpe for mg performed via peripheral (n = 100) vs.Central venous access (n = 34) (62).Cohorts included tpe use under any mg treatment context.Rates of several specific aes were significantly lower for peripheral access: anemia or coagulopathy requiring transfusion (0 vs.9%, p = 0.015), deep vein thrombosis (0 vs.12%, p = 0.0033), arrhythmia (atrial fibrillation with rapid ventricular response: 1 vs.15%, p = 0.0041), and acute renal failure (0 vs.9%, p = 0.015).The retrospective analysis of tpe timing within hcupnis found that the rates of several major ae categories were lower in early tpe (0¿2 days from admission, n = 870) vs.Delayed tpe (>2 days from admission, n = 183) (63).Specifically, the rates of cardiac complications (11.8 vs.24.6%, p < 0.0001), systemic infections (2.9 vs.7.7%, p < 0.001), and acute renal failure (1.0 vs.3.8%, p = 0.009) were all statistically lower when tpe was performed early.The adjusted odds ratio for any complication from the above categories showed a significant increase in risk when tpe treatment was delayed (odds ratio delayed/early: 1.49, p < 0.0001).Cobe spectra and spectra optia apheresis systems as noted for efficacy andmortality, data comparing other adverse events associated with different tpe systems was not found in published literature.Tables 8¿11 include adverse event data from several studies captured in this report that used the spectra systems, cobe spectra and spectra optia apheresis systems, exclusively (5, 62, 64, 70) or as one of two cited systems (51, 69).Safety findings from studies exclusively using cobe spectra and spectra optia apheresis systems in comparison to ivig (5, 72) and that used cobe spectra apheresis system exclusively in comparing between peripheral and central venous access (62) have been described in previous sections.Safety data in other tpe optimization studies using cobe spectra apheresis system reported higher rates of several aes under certain conditions, but differences did not reach statistical significance in any case (64, 69, 70).Lastly, in a retrospective analysis comparing tpe vs.Immunoadsorption in acute mg from an institution that utilized cobe spectra apheresis system as one of its two tpe systems, a higher overall adverse event rate was reported with tpe (36.9 vs.4.2%, p < 0.05) (51).Other than pneumonia, for which there was no significant difference between the two treatments, rates of specific aes were not reported.This systematic literature review and meta-analysis of treatment options showed that there was a higher response rate with tpe than ivig in acute mg patients and patients undergoing thymectomy.There was no difference in mortality between the two treatment options.Our findings highlight the need for additional randomized clinical trials in these patients with mg.The devices terumo bct manufactures to collect, separate, and store blood products are terminally sterilized to a sterility assurance level (sal) of
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