Improved Outcome up to Ten Years after Intravenous Immunoglobulin Therapy in Patients with Dilated Cardiomyopathy.

We aimed to investigate the efficacy and safety profile of high-dose intravenous immunoglobulin (HD-IVIG) therapy in patients with severe systemic lupus erythematosus (SLE), inflammatory muscle disease (IMD), Wegener's granulomatosis (WG), and/or concurrent infection who failed to respond to standard therapies. We evaluated the records of eight patients with SLE, eight with IMD, and four with WG who were treated with HD-IVIG (2 g/kg per month for 1-12 months) for active disease in 19 patients and concurrent infection in three (mycobacterial in two with SLE and cytomegaloviral in one with WG). Systemic lupus erythematosus disease activity index (SLEDAI) scores before and after HD-IVIG were statistically analysed. Remission was achieved in 14 cases (70%). The SLEDAI scores significantly decreased in patients with SLE (P=0.02). No serious side effect was observed. High-dose IVIG may be used as an adjunctive treatment in connective tissue diseases that do not respond to standard therapies or as alternative treatment for patients with concurrent severe infections or for whom immunosuppressives are contraindicated.

Thromboembolic complications of intravenous immunoglobulin therapy in patients with neuropathy: A two-year study

To evaluate the utility of different outcome measures to monitor dose adjustment of intravenous immunoglobulin (IVIg) therapy in patients with chronic inflammatory neuropathy (CIN). We assessed the adjustment of IVIg maintenance therapy in 20 patients (10 CIDP and 10 MMN) by regularly monitoring grip strength (GS) using a Martin Vigorimeter, RODS, and quality of life using the SF-36 questionnaire. These measures were regularly performed by the patient at home. We also assessed the extended MRC sumscore (eMRC sumscore) at each outpatient visit for IVIg infusion. We also enrolled 30 healthy controls to measure any possible training effect of GS with time and to analyze random fluctuation of GS. Clinically relevant change was detected by eMRC sumscore in 14 (93%) patients, by RODS in 11 (73%) patients, and by GS in 8 (53%) patients. Early sensitivity was greatest for RODS (73%), followed by GS (53%), and eMRC sumscore (27%). This differed from CIDP, with an early change in RODS in 100% of patients, and MMN with an early change in GS in 75%. None of the outcome measures alone was sufficient to detect clinically significant changes in all patients. Home monitoring of outcome measures objectively assisted clinical decision during individualization of IVIg treatment. We recommend a multimodal approach using different outcome measures to monitor the individual patient with CIN.

“Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy,” by Geerts et al., compared the administration of IVIG to placebo for patients with idiopathic small fiber neuropathy (SFN) and found no significant difference in the Pain Intensity Numerical Rating Scale score. In the October 19th Editors' Note, we summarized an exchange about these findings between Wilder-Smith and Spoendlin and Faber (a coauthor on the article).[1][1] Wilder-Smith and Spoendlin worried that this article may inappropriately dissuade clinicians from giving IVIG to patients with autoimmune SFN. They asked the authors to (1) provide additional data on the patients who were excluded because of autoimmune disease and (2) perform subgroup analysis based on symptom duration because patients with shorter duration of symptoms may be more likely to benefit from IVIG. Faber responded that 193 of 257 (75%) patients screened for enrollment were excluded; 41 had known autoimmune conditions. Faber agreed that a randomized study on the impact of IVIG on autoimmune SFN is needed. Because 75% of patients who were screened were excluded, Wilder-Smith and Spoendlin suggested that the study population does not reflect the population of patients with SFN routinely seen in clinical practice. They also requested additional information about the excluded patients and more clinical data for all screened patients, and further underscored the potential benefit for IVIG in patients with autoimmune SFN. In response, Faber et al. provided a table detailing the explanations for exclusion and noted that their exclusion rate is on par with the median exclusion rate for randomized-controlled trials (77%). They also reiterated that their focus was on patients with idiopathic SFN, not patients with autoimmune SFN, and that their findings indicate IVIG is not beneficial for this select patient population. However, they agreed that a future randomized-controlled trial is needed to evaluate the role of IVIG in autoimmune SFN. “Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy,” by Geerts et al., compared the administration of IVIG to placebo for patients with idiopathic small fiber neuropathy (SFN) and found no significant difference in the Pain Intensity Numerical Rating Scale score. In the October 19th Editors' Note, we summarized an exchange about these findings between Wilder-Smith and Spoendlin and Faber (a coauthor on the article).1 Wilder-Smith and Spoendlin worried that this article may inappropriately dissuade clinicians from giving IVIG to patients with autoimmune SFN. They asked the authors to (1) provide additional data on the patients who were excluded because of autoimmune disease and (2) perform subgroup analysis based on symptom duration because patients with shorter duration of symptoms may be more likely to benefit from IVIG. Faber responded that 193 of 257 (75%) patients screened for enrollment were excluded; 41 had known autoimmune conditions. Faber agreed that a randomized study on the impact of IVIG on autoimmune SFN is needed. Because 75% of patients who were screened were excluded, Wilder-Smith and Spoendlin suggested that the study population does not reflect the population of patients with SFN routinely seen in clinical practice. They also requested additional information about the excluded patients and more clinical data for all screened patients, and further underscored the potential benefit for IVIG in patients with autoimmune SFN. In response, Faber et al. provided a table detailing the explanations for exclusion and noted that their exclusion rate is on par with the median exclusion rate for randomized-controlled trials (77%). They also reiterated that their focus was on patients with idiopathic SFN, not patients with autoimmune SFN, and that their findings indicate IVIG is not beneficial for this select patient population. However, they agreed that a future randomized-controlled trial is needed to evaluate the role of IVIG in autoimmune SFN. [1]: #ref-1

Kawasaki disease, which is characterised by systemic vasculitides accompanied by acute fever, is regularly treated by intravenous immunoglobulin to avoid lesion formation in the coronary artery; however, the mechanism of intravenous immunoglobulin therapy is unclear. Hence, we aimed to analyse the global expression profile of serum exosomal proteins before and after administering intravenous immunoglobulin. Two-dimensional electrophoresis coupled with mass spectrometry analysis was used to identify the differentially expressed proteome of serum exosomes in patients with Kawasaki disease before and after intravenous immunoglobulin therapy. Our analysis revealed 69 differential protein spots in the Kawasaki disease group with changes larger than 1.5-fold and 59 differential ones in patients after intravenous immunoglobulin therapy compared with the control group. Gene ontology analysis revealed that the acute-phase response disappeared, the functions of the complement system and innate immune response were enhanced, and the antibacterial humoral response pathway of corticosteroids and cardioprotection emerged after administration of intravenous immunoglobulin. Further, we showed that complement C3 and apolipoprotein A-IV levels increased before and decreased after intravenous immunoglobulin therapy and that the insulin-like growth factor-binding protein complex acid labile subunit displayed reverse alteration before and after intravenous immunoglobulin therapy. These observations might be potential indicators of intravenous immunoglobulin function. Our results show the differential proteomic profile of serum exosomes of patients with Kawasaki disease before and after intravenous immunoglobulin therapy, such as complement C3, apolipoprotein A-IV, and insulin-like growth factor-binding protein complex acid labile subunit. These results may be useful in the identification of markers for monitoring intravenous immunoglobulin therapy in patients with Kawasaki disease.

“Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy” by Geerts et al. compared the administration of IVIG with placebo for patients with idiopathic small fiber neuropathy (SFN) and found no significant difference in the Pain Intensity Numerical Rating Scale score. We summarized (1) an exchange about these findings between Wilder-Smith and Spoendlin and Faber (a coauthor on the article) in the October 19, 2021, Editors' Note and (2) an exchange between Wilder-Smith et al. and Faber et al. in the January 18, 2022, Editors' Note.[1][1],[2][2] Oaklander et al. now comment that while the trial used a subjective outcome (pain intensity), an objective assessment (such as autonomic function test scores) could have enhanced the methodology. They also advocate against the extrapolation of these results to all patients with SFN, noting that patients with autoimmune disorders who may benefit from IVIG may not be readily apparent, so it is beneficial to create guidelines triaging patients with SFN who may benefit from a time-limited trial of IVIG. Finally, they express concern that payors may deny treatment to some patients who could benefit, particularly those who are immune-mediated. Faber et al. respond that changes in the Pain Intensity Numerical Rating Scale score are clinically relevant and the sensitivity of autonomic function testing results in isolation to detect autonomic dysfunction in SFN is low in clinical practice. They agree that patients with immune-mediated SFN may benefit from IVIG and emphasize that their study was not intended to focus on that patient population. However, they suggest that randomized studies with valid and reliable outcome measures are needed to evaluate the role of IVIG in patients with SFN that could potentially be immune-mediated. “Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy” by Geerts et al. compared the administration of IVIG with placebo for patients with idiopathic small fiber neuropathy (SFN) and found no significant difference in the Pain Intensity Numerical Rating Scale score. We summarized (1) an exchange about these findings between Wilder-Smith and Spoendlin and Faber (a coauthor on the article) in the October 19, 2021, Editors' Note and (2) an exchange between Wilder-Smith et al. and Faber et al. in the January 18, 2022, Editors' Note.1,2 Oaklander et al. now comment that while the trial used a subjective outcome (pain intensity), an objective assessment (such as autonomic function test scores) could have enhanced the methodology. They also advocate against the extrapolation of these results to all patients with SFN, noting that patients with autoimmune disorders who may benefit from IVIG may not be readily apparent, so it is beneficial to create guidelines triaging patients with SFN who may benefit from a time-limited trial of IVIG. Finally, they express concern that payors may deny treatment to some patients who could benefit, particularly those who are immune-mediated. Faber et al. respond that changes in the Pain Intensity Numerical Rating Scale score are clinically relevant and the sensitivity of autonomic function testing results in isolation to detect autonomic dysfunction in SFN is low in clinical practice. They agree that patients with immune-mediated SFN may benefit from IVIG and emphasize that their study was not intended to focus on that patient population. However, they suggest that randomized studies with valid and reliable outcome measures are needed to evaluate the role of IVIG in patients with SFN that could potentially be immune-mediated. [1]: #ref-1 [2]: #ref-2

In “Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy,” Geerts et al. report no significant difference in Pain Intensity Numerical Rating Scale score for patients with idiopathic small fiber neuropathy (I-SFN) 12 weeks after randomized administration of IVIG or placebo. In “Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy,” Geerts et al. report no significant difference in Pain Intensity Numerical Rating Scale score for patients with idiopathic small fiber neuropathy (I-SFN) 12 weeks after randomized administration of IVIG or placebo.

Comparison of high-dose and low-dose intravenous immunoglobulin therapy in patients with primary immunodeficiency diseases

Intravenous immunoglobulin (IVIG) therapy is widely used in immune-mediated diseases as an immunomodulatory agent and is considered to be a safe biologic agent. To determine the frequency of adverse events associated with IVIG therapy in patients with pemphigus and pemphigoid. We retrospectively reviewed data on patients treated with IVIG for pemphigus and pemphigoid over a 10 year period. Patients had pemphigus vulgaris, pemphigus foliaceus, mucous membrane pemphigoid, or bullous pemphigoid. IVIG was given according to a published protocol at a dose of 2 g/kg administered over 3-5 days at prescribed intervals. Patient records were reviewed for information on sex, age, duration of treatment, number of cycles given, number of days each patient received IVIG, weight of each patient, IVIG dose each patient received per infusion, and early or delayed adverse effects reported by patients or observed by healthcare providers. We identified 9892 infusions given to 174 patients. Headaches were the most common adverse effects; they were observed during 886 (8.9%) infusions and involved 123 (70.6%) patients. The incidence of other minor adverse effects, including fatigue, nausea, vomiting, chills, urticaria, swollen glands, hoarseness, thoracic discomfort, and palpitations, was 0.57-3.4% per infusion and 0.04-1.3% per patient. Hoarseness of voice and swelling of cervical lymph nodes have not been previously reported. Acute renal failure occurred in one patient and was the only major adverse effect observed. None of the patients required hospitalization, and there were no deaths. Adverse events associated with IVIG therapy are usually mild and self-limiting. The incidence of serious adverse events is low. Identification of risk factors and close monitoring of high-risk patients throughout the therapy are likely to decrease the occurrence of rare serious and less likely fatal adverse effects.

The aim of this study was to investigate changes in CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs) throughout the clinical course of Kawasaki disease (KD) and correlations with response to intravenous immunoglobulin (IVIg) therapy. Participants comprised 18 patients who fulfilled the diagnostic criteria for KD and 20 healthy subjects. Expressions of CD25 and FOXP3 among all CD4(+) T cells in peripheral blood mononuclear cells were analyzed by flow cytometry before and 7 and 30 days after IVIg therapy. Before treatment, percentages of CD4(+)CD25(+)FOXP3(+) Tregs among total CD4(+) Tregs were significantly lower among KD patients (4.19 %; range, 0.16-8.11 %) than among healthy subjects (7.32 %; 4.18-13.42 %; P = 0.0001). Both percentages and absolute numbers of CD4(+)CD25(+)FOXP3(+) Tregs on day 7 after IVIg therapy were significantly increased compared with values before treatment (8.02 % (range, 0.51-12.6 %) vs. 4.19 % (range, 0.16-8.11 %), P = 0.0005; 93.25/ μL (range, 6.67-258.05) vs. 41.85/ μL (range, 0.44-160.62), P < 0.0001, respectively). Moreover, percentages and absolute numbers of CD4(+)CD25(+)FOXP3(+) Tregs before treatment were significantly lower in the IVIg-resistant group than in the IVIg-sensitive group (0.18 % (range, 0.16-3.34 %) vs. 4.52 % (range, 2.8-8.11 %), P = 0.0022; 0.68/μL (range, 0.44-53.81) vs. 51.66/μL (range, 2.88-160.62), P = 0.0098, respectively). The frequency of CD4(+)CD25(+)FOXP3(+) Tregs in four of the five IVIg-resistant patients at diagnosis was more than 3 standard deviations below that in healthy subjects. Two of these four patients displayed coronary abnormalities, and one of these two patients developed coronary aneurysm. Lack of CD4(+)CD25(+)FOXP3(+) Tregs before treatment may predict resistance to IVIg therapy in patients with KD.

We would like to respond to the comments made by Drs. Wilder-Smith and Spoendlin on our study1 related to the heterogeneous group of patients with idiopathic small fiber neuropathy (I-SFN), who might benefit from intravenous immunoglobulin (IVIg) therapy. Before study entry, all patients had a diagnostic SFN workup, which includes tests for several associated conditions, as mentioned in the inclusion criteria.1 Of 257 patients, there were 193 patients who did not meet the inclusion criteria, 41 of which (16%) were excluded because of known autoimmune conditions, which is in line with previous findings.2 Future studies are needed to definitely determine whether IVIg may have a therapeutic role in the treatment of autoimmune conditions that cause SFN. There are some open-label clinical studies suggesting a potential therapeutic role,3,4 but stronger evidence from a randomized study is needed. Our RCT showed that IVIg treatment had no significant effect on pain in patients with painful I-SFN and should therefore be discouraged.

BackgroundHemolytic anemia is a rare but reported side effect of intravenous immunoglobulin (IVIG) therapy. The risk of significant hemolysis appears greater in those patients who receive high dose IVIG. The etiology is multifactorial but may relate to the quantity of blood group antibodies administered via the IVIG product.FindingsWe describe 4 patients with significant hemolytic anemia following treatment with IVIG for Kawasaki disease (KD). Direct antibody mediated attack as one of the mechanisms for hemolysis, in this population, is supported by the demonstration of specific blood group antibodies in addition to a positive direct antiglobulin test in our patients.ConclusionsClinicians should be aware of this complication and hemoglobin should be closely monitored following high dose IVIG therapy.

Intravenous immunoglobulin therapy in patients with multiple mucosal involvement in mucous membrane pemphigoid.

P 46. Assessment of individualized treatment decisions for intravenous immunoglobulin therapy in patients with chronic immune-mediated neuropathies: observational study design and progress

Intravenous immunoglobulin therapy in patients with Ocular–Cicatricial pemphigoid: A long-term follow-up