Aislinn Antrim, Assistant Editor

An updated review of 12 clinical trials has found that in severe cases of Guillain-Barre syndrome (GBS), intravenous immunoglobulin (IVIG) administered within 2 weeks from onset can hasten recovery as much as plasma exchange, which has been shown to improve recovery in earlier studies.

GBS is an acute, paralyzing, inflammatory peripheral nerve disease that causes weakness, numbness, and difficulty breathing. The study, published by the Cochrane Library, found that in 25% of patients, the disease is sufficiently severe to require artificial ventilation and between 3.5% and 12% of patients die of complications during the acute stage of the disease. The current favored hypothesis is that this is caused by an autoimmune response directed against antigens in the peripheral nerves, triggered by a bacterial or viral infection.

Earlier reviews of treatment options have found that plasma exchange, in which a person’s plasma is replaced with a substitute to remove antibodies, works better than supportive care alone when treating patients with GBS. Corticosteroids have been used to treat the disease, although an updated systematic review concluded that they offered no benefit besides a possible faster recovery shown in a trial in which IV methylprednisolone was administered in combination with IVIG.

To investigate the impact of IVIG, investigators reviewed 12 clinical trials, 7 of which compared IVIG with plasma exchange in 623 severely affected participants. The other 5 trials had available outcomes for 536 participants but did not have a statistically significant mean difference of change in a 7-grade disability scale after 4 weeks when comparing IVIG with plasma exchange treatment.

Three studies included a total of 75 children and suggested that IVIG significantly hastens recovery times compared with supportive care alone. The primary outcome was an improvement in disability grade 4 weeks after randomization, and although it was only available for 1 trial with 21 mildly affected children, it showed significantly more improvement in disability grade after 4 weeks with IVIG.

On trial compared plasma exchange followed by IVIG with plasma exchange alone in 249 participants and found that the mean grade improvement was 0.2 more in the combined treatment group than in the group that only received plasma exchange. Although the authors said this was not clinically significant, it does not exclude the possibility of significant benefit with IVIG treatment. A separate trial compared immunoabsorption followed by IVIG with immunoabsorption alone and did not reveal any significant extra benefit from the combined treatment.

The investigators noted that 5 of the trials comparing IVIG and plasma exchange measured change in disability and found that the 2 treatments produced a similar amount of improvement in the 536 participants. The authors said this evidence was of moderate quality and harmful effects were no more frequent with either plasma exchange or IVIG, but patients were more likely to finish the course of IVIG.

Based on these findings, the authors said that if IVIG is commenced within 2 weeks from the onset of GBS it can hasten recovery as much as plasma exchange, which is known to be more effective than supportive care alone. Moderate quality evidence suggested that there is no difference in the frequency of adverse events and that treatment with IVIG is significantly more likely to be completed than plasma exchange treatment.

The investigators concluded that further trials should investigate whether IVIG helps in mild GBS cases and in disease that has lasted more than 2 weeks and said investigators should also work to establish an optimal dose.

Hughes R, Swan A, van Doorn P. Intravenous immunoglobulin for Guillain-Barre syndrome. Cochrane Database Systematic Review; September 19, 2014. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781841/

Articles

If IVIG is commenced within 2 weeks from the onset of Guillain-Barre syndrome it can hasten recovery as much as plasma exchange, study indicates.

Study: Intravenous Immunoglobulin Hastens Recovery of Early Onset Guillain-Barre

A systematic review of 11 studies found no clear therapeutic benefit of intravenous immunoglobulin (IVIG) for the prevention of postnatal relapses of multiple sclerosis (MS), despite being routinely recommended by some physicians, according to the study authors.

MS is a chronic neurological condition that is predominant among women and has frequent onset during fertile age, making its effects on pregnancy important for research. Despite this need for more research, the investigators said the obvious ethical implications of clinical trials in pregnant women make research difficult, leaving only retrospective observational data and meta-analyses available.

The disease is frequently characterized by demyelination in the central nervous system and can include unilateral vision loss, double vision, limb weakness, sensory abnormalities, lack of coordination, and unsteadiness when walking. All of these issues can impact pregnant women, and the investigators said one of the main concerns in this patient population is the increased risk of a demyelinating relapse after delivery.

The systematic review included 11 articles, although only 6 had data to compare the effect of IVIG on the outcome. The other 5 articles were analyzed and presented using qualitative synthesis. The articles had a total of 380 patients who received immunoglobulin after pregnancy to reduce the number of postpartum relapses and 72 participants were included in the quantitative data analysis.

Of these 72 patients, 11 relapsed within the first 6 months postpartum. The control group included 132 patients who did not receive IVIG, 65 of whom relapsed during the first 6 months after delivery. The investigators found that the odds of relapse postpartum within the first 6 months after delivery were 68% lower in the treatment group than in the control group.

The investigators noted that earlier studies have not always come to the same conclusion, however, making systematic reviews essential. For example, a 1996 cohort study by Achiron et al assessed the effects of IVIG at 0.4 g per day for 5 consecutive days during the first week after gestation and with follow-up administration at 6 and 12 weeks. Of the 3 patients who received this regimen, none relapsed during the first 6 months after gestation, while 12 non-IVIG treated patients relapsed during the same period.

In another study conducted by Hellwig et al, investigators studied the effects of IVIG, no treatment, and conventional disease-modifying therapy in 124 pregnant women. Group 1 received 1 of the 3 different treatment regimens, group 2 received no postpartum treatment, and group 3 received conventional disease-modifying treatment 2 weeks after birth. According to their results, the use of IVIG was not shown to be significantly superior to the other alternatives.

Finally, a dose comparison study of IVIG in postpartum MS compared different IVIG doses in 173 pregnancies. Group 1 received 150 mg/kg on day 1 followed by placebo infusions on days 2 and 3, while group 2 received 450, 300, and 150 mg/kg on days 1, 2, and 3, respectively. After this regimen, both groups received 150 mg/kg 5 times at 4-week intervals. In the first 3 months postpartum, the investigators found no significant differences in relapse rates between the 2 groups.

Based on this review, the authors said the quantitative and qualitative analyses could not establish any advantage of using IVIG in this patient population. They said the range of doses, therapeutic schemes, timing of treatment, and assessment of relapses over time presented serious limitations in reaching conclusions and consensus among the studies and the authors said they could not support the recommendation of IVIG.

Rosa G, O’Brien A, Nogueira E, et al. There is no benefit in the use of postnatal intravenous immunoglobulin for the prevention of relapses of multiple sclerosis: findings from a systematic review and meta-analysis. 

https://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-282X2018000600361&lng=en&nrm=iso&tlng=en

Researchers find no clear therapeutic benefit of intravenous immunoglobulin for the prevention of postnatal relapses of multiple sclerosis. 

Study Finds No Benefit to Postnatal IVIG in Preventing Multiple Sclerosis Relapses

New exploratory analyses have found that a longer interval between the first and second standard dose of Oxford University’s COVID-19 vaccine candidate results in higher efficacy compared to a shorter 6-week interval.

Investigators also found that the first dose offers significant protection in the 3 months between doses, with 76% efficacy. The results, published in 

, suggest that the interval between doses can be safely extended given the protection offered by the first dose, which may allow countries to vaccinate a larger proportion of the population more rapidly, according to the study.

The exploratory analyses included 17,178 participants as well as updated estimates of overall vaccine efficacy against symptomatic disease for 2 standard doses. According to a press release, there were no hospitalizations or deaths among those receiving the vaccine from 22 days after the first dose, compared with 15 cases in the control group. The study authors said this provides further support for the vaccine candidate and its extended intervals between doses.

“Vaccine supply is likely to be limited, at least in the short term, and so policy-makers must decide how best to deliver doses to achieve the greatest public health benefit,” said lead author Andrew Pollard, BSc, MBBS, PhD, in the press release. “Where there is a limited supply, policies of initially vaccinating more people with a single dose may provide greater immediate population protection than vaccinating half the number of people with 2 doses.”

Following regulatory approval, the investigators said it is important to understand the best dose interval in order to ensure optimal roll-out plans. Factors associated with this include the effect of different intervals on protection after the second dose, and the risk of infection between doses either due to lower efficacy of a single dose or rapid waning of efficacy while waiting for the second dose, according to the study.

The investigators combined data from randomized controlled trials in the United Kingdom, Brazil, and South Africa. Participants were aged 18 years or older and either received 2 doses of the Oxford COVID-19 vaccine candidate or a control vaccine and saline combination. In the United Kingdom trial, a subset of participants received a lower dose of the vaccine as their first dose.

The primary outcome was the number of symptomatic COVID-19 cases in the control and vaccine groups occurring more than 14 days after the second dose. The exploratory analyses were requested by regulators and policymakers. The investigators also conducted an analysis to establish the impact of 1 or 2 doses of the vaccine on reducing all COVID-19 cases as an indicator of how the vaccine might reduce transmission.

According to the press release, participants who were given their doses 12 or more weeks apart had 81% protection, compared to 55% efficacy for those given their 2 doses less than 6 weeks apart. Efficacy results were supported by immune response results in adults between 18 and 55 years of age, which showed that binding antibody responses were more than 2-fold higher in the group having their 2 vaccines with a longer delay.

Following a single standard vaccine dose, efficacy from 22 days to 3 months after vaccination was 76%. Modeling indicated that this protection did not reduce over the 3 months, and antibody levels against the SARS-CoV-2 spike protein remained at similar levels throughout the interval period.

“This latest analysis confirms our previous findings of the higher efficacy of a low- then standard-dose regimen,” said Merryn Voysey, PhD, lead statistician at the Oxford Vaccine Group, in the press release. “However, with additional data available, we have found that the enhanced efficacy and immunity may be partly driven by the longer interval between doses that was common in this trial group.”

The investigators noted that it is unclear how long protection with a single dose of the vaccine might last because the trial results are limited to the 3 months maximum. For this reason, the investigators said a second dose of the vaccine is still recommended.

“This further supports the relationship we have found between vaccine interval and efficacy in those receiving 2 standard doses, which is the preferred regimen because there are more data to support its use, and because it is simpler to deliver a vaccine program when the same vaccine is given for both doses,” Voysey said.

The Lancet: 3-month interval between first and second dose of Oxford COVID-19 vaccine results in higher vaccine efficacy than 6-week interval [news release]. EurekAlert; February 19, 2021. 

https://www.eurekalert.org/pub_releases/2021-02/tl-pss021921.php

The first vaccine dose alone offered strong protection against COVID-19, with efficacy that did not decline over the 3 months between doses.
 

Study: 3-Month Interval Between Oxford COVID-19 Vaccine Doses Results in Higher Efficacy

In a press briefing Tuesday afternoon, President Joseph Biden said new developments in COVID-19 vaccine production will provide enough vaccine doses for every adult in the United States by the end of May, 2 months earlier than originally predicted.

 As part of this acceleration, in a deal brokered by the Biden administration, Merck will begin manufacturing Johnson & Johnson’s COVID-19 vaccine in an effort to ramp up production.

“Today, we’re announcing a major step forward,” Biden said in the press conference. “Two of the largest health care and pharmaceutical companies in the world, that are usually competitors, are working together on the vaccine.”

Biden described this as the type of collaboration seen during World War II, which is in line with his descriptions of the COVID-19 response as a “wartime effort.” He also announced that the Johnson & Johnson facilities will begin operating around the clock and some critical materials and machinery will be expedited through the Defense Production Act.

, White House officials began looking for additional manufacturing capacity early in the administration, after realizing that Johnson & Johnson had fallen behind in vaccine production. As one of the world’s largest vaccine manufacturers, Merck offered an opportunity to significantly increase supply.

As part of the deal, Merck will dedicate 2 of its United States facilities to producing Johnson & Johnson’s vaccine. One facility will provide “full-finish” services, the last stage of the process during which the vaccine itself is placed in vials and packaged.

 The other will produce the vaccine itself and could perhaps even double the amount that Johnson & Johnson could produce on its own, according to the 

Despite the encouraging plan, officials cautioned that it could easily take 2 months to get the “full-finish” plant ready and a few more months to equip the second plant.

In addition to increasing vaccine supply, Biden emphasized the need for vaccinators. As part of the Federal Retail Pharmacy Program, he said the administration has sent millions of vaccines to more pharmacies across the country.

“We’ve sent millions of vaccines to over 7000 pharmacies to make it easier for folks to get their COVID-19 vaccination shot like they would their flu shot,” Biden said.

Johnson & Johnson’s vaccine was awarded an 

 on February 27, based on an FDA analysis that found the single-shot vaccine provides strong protection against severe disease and may reduce transmission. Because the vaccine only requires 1 shot, experts say it could enable vaccination of hard-to-reach populations, such as homeless individuals and those in rural communities.

“We should all be encouraged by this news of a third safe and highly effective COVID-19 vaccine,” Biden said in the press briefing.

The vaccine can be stored at standard refrigeration temperatures for up to 3 months, which could also help expand access. In an interview with 

, Amesh Adalja, MD, FIDSA, FACP, FACEP, a senior scholar at the Johns Hopkins Center for Health Security, said easier storage could be a significant help in the roll-out process.

“The easier it is to store a vaccine, the more versatile it can be,” Adalja said. “So, with the Johnson & Johnson vaccine having an even less stringent cold chain [than Pfizer and BioNTech’s vaccine], you can really get that into pharmacies, you can even do door-to-door vaccination with something like this with mobile vaccination units. You could do a lot more with a vaccine where you don’t have to worry about storage.”

Despite the encouraging developments, Biden said actions such as social distancing and mask wearing are still essential.

“Now is not the time to let our guard down,” he concluded in the press briefing. “People’s lives are at stake.”

McGinley L, Rowland C. Biden to announce ‘historic partnership’: Merck will help make Johnson & Johnson coronavirus vaccine, officials say. 

https://www.washingtonpost.com/health/2021/03/02/merck-johnson-and-johnson-covid-vaccine-partnership/

FDA Approves Emergency Use Authorization for Johnson & Johnson Single-Dose COVID-19 Vaccine. 

https://www.pharmacytimes.com/news/fda-approves-emergency-use-authorization-for-johnson--johnson-single-dose-covid-19-vaccine

Expert: Johnson & Johnson Vaccine ‘May Be a Vaccine That Many Americans Have Access to Very Easily, Very Close to Their Home’. 

https://www.pharmacytimes.com/interviews/expert-the-johnson--johnson-vaccine-may-be-a-vaccine-that-many-americans-have-access-to-very-easily-very-close-to-their-home

President Joseph Biden announced a partnership between Merck and Johnson & Johnson, in which 2 of Merck’s facilities will begin producing the Johnson & Johnson COVID-19 vaccine. 
 

Biden Says US Will Have Enough COVID-19 Vaccines for Every Adult By End of May

Although subcutaneous immunoglobulin (SCIG) is an option for maintenance therapy in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), a study analysis published in the 

 shows that more participants showed improved disability at 24 weeks when receiving intravenous immunoglobulin (IVIG).

CIDP is an acquired neurological disorder characterized by weakness and impaired sensory function evolving over 2 months or more, loss or a significant decrease in deep tendon reflexes, and electrophysiological evidence of peripheral nerve demyelination. According to the study authors, early diagnosis and treatment of CIDP is essential to avoid irreversible damage and disability.

IVIG is an option for both first-line and maintenance CIDP therapy, and the 2018 FDA approval of SCIG in this population provides more treatment options for maintenance therapy. Other first-line options with proven efficacy include corticosteroids and plasmapheresis. The authors said these different options for IG administration necessitate more information to assist clinicians and patients when choosing their approach.

Based on 5 randomized, placebo-controlled trials between 1993 and 2008, investigators have established the efficacy and safety of IVIG. According to the authors, the most informative trial was Intravenous Immunoglobulin for the Treatment of Chronic inflammatory Demyelinating Polyradiculoneuropathy (ICE study), which compared IVIG administered as a 2 g/kg loading dose followed by a 1 g/kg maintenance dose every 3 weeks to a placebo. The study included 117 patients and had a primary outcome measure of improvement from baseline in disability by 6 weeks and maintained through 24 weeks.

According to the analysis, the percentage of patients with improved disability at 24 weeks was significantly greater in the IVIG group compared with the placebo group (54% and 21%, respectively). Furthermore, 60% of IVIG responders achieved maximal response by week 6, in addition to significant improvements in muscle strength and grip strength.

Finally, the authors found 55% of patients receiving IVIG reported a drug-related adverse event (AE), compared with 17% of patients receiving the placebo. The most commonly reported IVIG-associated adverse events were headache, pyrexia, and hypertension. Serious AEs were reported in 5% of IVIG patients and 8% of placebo patients.

Despite these encouraging findings for IVIG treatment, the review authors said that the availability of both IV and SC routes has made personalization of treatment more important than ever.

“While selection of IVIG or SCIG is ultimately a choice best left to the discretion of each patients and their treating physician, several factors warrant consideration so that patients can make informed decisions that best balance their needs, preferences, and lifestyles,” the authors wrote.

These factors include pharmacokinetics, AE profiles, the site of care available to the patient, dosing and frequency of administration, infusion rate and duration, and patient preference variables. Clinicians should consider and discuss all of these factors with patients in order to ensure that every patient is treated individually and receives the care that works best for them.

“The decision to use SCIG and IVIG is one that is best individualized to each patient’s disease characteristics, treatment goals, and lifestyle,” the authors concluded. “There is no ‘best’ method to determine which route of administration is optimal for every patient. Health care providers are uniquely positioned to help patients work through these complex issues. Ultimately, the decision is a personal one that ideally maximizes efficacy, tolerability, and quality of life.”

Allen J, Gelinas D, Freimer M, Runken M, and Wolfe G. Immunoglobulin administration for the treatment of CIDP: IVIG or SCIG? 

https://www.jns-journal.com/article/S0022-510X(19)30429-0/fulltext

The availability of both intravenous and subcutaneous routes of immunoglobulin has made personalization of treatment more important than ever.
 

Researchers Recommend IV Immunoglobulin for Chronic Inflammatory Demyelinating Polyneuropathy

New research suggests that an increase in red blood cells that raises the risk of blood clots may be a dangerous adverse effect (AE) of testosterone therapy for transgender men, according to a study published in the Endocrine Society’s 

Journal of Clinical Endocrinology & Metabolism

Gender diverse people make up an estimated 0.6% of the US population, according to the study authors, and are defined as having a gender identify that is not aligned with their sex recorded at birth. As part of their gender-affirming treatment, transgender men often undergo testosterone therapy, although erythrocytosis is a common AE that can increase the risk of blood clots, heart attack, or stroke.

“Erythrocytosis is common in transgender men treated with testosterone, especially in those who smoke, have high body mass index (BMI), and use testosterone injections,” said lead study author Milou Cecilia Madsen, MD, in a press release. “A reasonable first step in the care of transgender men with high red blood cells while on testosterone therapy is to advise them to quit smoking, switch injectable testosterone to gel, and if BMI is high, to lose weight.”

To examine the prevalence and determinants of erythrocytosis in this population, investigators conducted a 20-year follow-up study in 1073 adult transgender men who started testosterone therapy and had monitoring of hematocrit. According to the study results, erythrocytosis with a hematocrit of more than 0.50 occurred in 11% of participants, a measurement of more than 0.52 occurred in 3.7% of participants, and a measurement of more than 0.54 occurred in 0.5%.

Tobacco use, long-acting undecanoate injections, age at initiation of hormone therapy, BMI, and pulmonary conditions associated with erythrocytosis and polycythemia vera were all associated with a hematocrit greater than 0.50.

 Furthermore, the investigators found that hematocrit increased the most during the first year of testosterone therapy, going from 0.39 at baseline to 0.45 after 1 year. Although there was only a slight continuation of this increase over the following 20 years, the probability of developing erythrocytosis still increased by 10% after 1 year and by 38% after 10 years.

Based on these findings, the investigators said erythrocytosis is a common occurrence in transgender men using testosterone. In order to combat the condition, the study authors recommended avoiding risk factors such as smoking and switching to a transdermal administration route for testosterone.

Study finds risk factor for blood clots occurs in more than 10 percent of transgender men using testosterone [news release]. EurekAlert; February 18, 202 

https://www.eurekalert.org/pub_releases/2021-02/tes-sfr02152php

Madsen M, van Dijk D, Wiepjes C, et al. Erythrocytosis in a large cohort of trans men using testosterone: a long-term follow-up study on prevalence, determinants and exposure years. 

https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgab089/6138195

Investigators recommended avoiding risk factors such as smoking and switching to a transdermal administration route for testosterone.
 