Monthly Intravenous Immunoglobulin Research Articles

Infection Risk and Use of Prophylaxis with Anti-BCMA Bispecific T Cell Engagers and Belantamab Mafodotin for Patients with Relapsed and Refractory Multiple Myeloma

Introduction: BCMA targeted therapies have demonstrated single agent efficacy for patients with triple class exposed or refractory multiple myeloma (RRMM). Teclistamab and Belantamab Mafodotin (Belamaf) are currently approved for RRMM in Europe with several Bispecific T Cell Engagers (TCE) under investigation. However, whilst TCEs have higher response rates and progression free survival to Belamaf, adverse events, particularly infections may influence treatment choice particularly for frailer patients. Intravenous Immunoglobulin (IVIg) is recommended to prevent infections once IgG levels fall <4g/L or even as prophylaxis with anti-BCMA TCEs. Methods: This was a retrospective review of MM patients treated with anti-BCMA monotherapies at University College London Hospitals between 28/07/2015 and 15/06/2023. IVIg was given according to UK guidelines: IgG of <3g/L and recurrent infections/ one severe infection, despite 6 months of prophylactic antibiotics. IgG levels between 3-4g/L also required failure of a vaccine challenge. IVIg for asymptomatic patients was not permitted. Statistics was performed using GraphPad Prism. Results: 55 patients were treated with anti-BCMA monotherapies: 21 with TCE and 34 with Belamaf. The median age was 61 years (range 45-79), 43% female, 80% white and 5.6% Black. The median time from diagnosis to treatment was 5.8 years with a median of 5 prior lines (range 2-15). 51.9% of patients had high risk cytogenetics. Patients were a median of 59 years for TCE (range 47-73) vs 64 years (range 45-79) with Belamaf. Both groups had a median of 5 prior lines and a median Charlson co-morbidity index of 2, but 40% of TCE were classified frail by modified IMWG score vs 61.8% with Belamaf. CD38 exposure was 100% for TCE patients and 76% Belamaf. Severe hypogammaglobulinemia (<4g/L) at baseline prior to anti-BCMA treatment was present in 75% of TCE and 53% of Belamaf patients. Further significant reductions in median IgG levels occurred during treatment (TCE: 3.04g/L to 1.06g/L, p=0.01; Belamaf: 3.9g/L to 1.9g/L p=0.002). Nadir IgG levels were significantly lower with TCE than Belamaf (p=0.047). All patients received aciclovir prophylaxis, PJP prophylaxis (co-trimoxazole/ azithromycin) was given in 100% with TCE and 82% with Belamaf, with anti-fungal prophylaxis in 1 TCE patient. IVIg was used prior to anti-BCMA treatment in 3 patients (2 TCE, 1 Belamaf). Whilst on anti-BCMA treatment, IVIg was used in 38% for TCE and 5.9% for Belamaf. The risk for all grade infection per patient was 3.7 times higher for TCE vs Belamaf (increased risk TCE vs Belamaf: G1-2: 3.3, G3: 2.1, G4: 2.1). There was a total of 104 infection episodes, 57% with TCE, 43% with Belamaf (see Figure). The median time to first infection was 45 days for TCE and 34 days for Belamaf. Most infections were low grade with 20 patients having ≥1 infection (10/21 (48%) TCE, 10/34 (29%) Belamaf). At Grade 1-2, there were 1.8 infections per patient for TCE vs 0.7 for Belamaf. For G3-5, 1.0 infections per patient vs 0.6 for Belamaf. There was 1 grade 5 infection with TCE, 0 for Belamaf. Respiratory infections predominated (TCE: 80% vs Belamaf: 73%) followed by urinary (TCE: 5% vs Belamaf 16%), blood (TCE 10% vs Belamaf 5.4%) and GI (TCE 3% vs Belamaf 5%). 96/ 104 infections were identified, most were viral (TCE 71% vs Belamaf 62%) with few fungal infections (6% vs 4%). More bacterial infections occurred with Belamaf possibly due to lower antibacterial prophylaxis and IVIg use (TCE: 23% vs Belamaf: 35%). Since commencing IVIg, 5 of 8 (63%) TCE patients had at least 1 infection, mainly viral. A median of 1 further infection (range 0-14) occurred over a median of 3.2m (range 0.6-28.3m) of monthly IVIg infusions. Routine blood viral PCR monitoring for CMV, EBV & Adenovirus was performed in 30% of patients. 13 (65%) of TCE patients had 197 blood viral PCR tests performed of which 3 patients (23%) tested positive (2x adenovirus and 1 CMV). Of these 2 (both adenovirus) had symptoms requiring intervention. Of the 8.8% of Belamaf patients tested, 0 were positive. Conclusions: Patients treated with Belamaf were frailer than those receiving TCE. Hypogammaglobulinemia was more profound with TCE and the per patient risk of infections was higher. IVIg use was substantially higher for TCE than Belamaf. Blood viral PCR monitoring for TCE patients only detected symptomatic reactivations in 2 out of 13 patients suggesting this was an infrequent event.

Navigating the management complexity in long-term asymptomatic immunodeficiency

Background: Common variable immunodeficiency disorder (CVID) is a condition associated with recurrent infections and non-infectious outcomes, including lung disease like bronchiectasis and granulomatous and lymphocytic interstitial lung diseases (GLILD), autoimmune disease, enteropathy, and lymphoma. Treatment involves initiation of replacement immunoglobulin (Ig), which is a lifelong commitment. Prior to Ig replacement, life expectancy for patients with CVID was less than 15 years. With replacement Ig, it has improved to over 50 years. In most cases, patients present to a clinician with a history of recurrent infections, and treatment is indicated. However, in patients with asymptomatic disease, the best timing to start treatment can be difficult to determine. Case: We present a case of an otherwise healthy male who had an incidental diagnosis of CVID. Results: Workup revealed hypogammaglobulinemia for over 30 year. Discussion: Though successful in reducing infections, Ig replacement can come with many side effects, as well as a heavy medical burden to the patient and the healthcare system. It is also a big life adjustment, and can greatly affect a patient's quality of life. In the military, a diagnosis of an immunodeficiency, and the need for monthly intravenous immunoglobulin (IVIG) can be detrimental to deployment readiness, and a patient's military career. Risks and benefits need to be weighed prior to initiating Ig therapy.

Poor Visual Outcome After First Attack in a Cohort of Patients With Myelin Oligodendrocyte Glycoprotein-Related Optic Neuritis.

Myelin oligodendrocyte glycoprotein-associated optic neuritis (MOG-ON) is typically a highly treatable condition that responds quickly to treatment with high doses of corticosteroids. We reviewed the cohort of patients with MOG-ON to identify patients who had poor visual outcome after the first attack despite rapid initiation of treatment. Records of all patients diagnosed with MOG-ON seen in a tertiary neuro-ophthalmology practice were reviewed to identify and describe those with poor visual recovery (final visual acuity of 20/200 or worse in at least one eye) after the first attack despite initiation of treatment within 1 week of symptoms onset. Two patients of 36 fulfilled inclusion criteria: both had bilateral severe optic neuritis at presentation, and both were seen within 7 days of symptoms onset and treated immediately with pulse doses of intravenous corticosteroids followed by very-slow oral taper. Plasma exchange (PLEX) was performed 2 weeks after symptoms onset in both patients because of poor response to steroids, followed by monthly intravenous immunoglobulin infusions. Despite the use of all available treatment modalities, final visual outcome was poor in both patients. In both patients, there was enhancement of intracanalicular portion of optic nerve in the worse-seeing eye. In this cohort of patients with MOG-ON, 2 (5.6%) had very poor visual outcome after the first attack despite immediate initiation of treatment with pulse doses of corticosteroids and subsequent treatment with PLEX. These cases highlight that despite immediate initiation and escalation of treatment, some patients with MOG-ON can have very poor visual outcomes after the initial attack that may be because of the involvement of the intracanalicular portion of the optic nerves.

Undermining Ulcers in Juvenile Dermatomyositis.

A 6-year-old boy with a history of refractory anti–transcription intermediary factor 1-γ (anti–TIF1-γ) juvenile dermatomyositis presented to the rheumatology clinic with skin ulcers of 10 days in duration. Physical examination revealed normal muscle for strength. Heliotrope rash, Gottron sign, and diffuse erythematous eruption on the neck, trunk, and buttocks were observed (Figs. 1A, B). No calcinosis cutis, and 2 ulcers (4 × 3 cm, 1 × 1 cm) on the left upper arm deep into the underlying biceps with well-circumscribed margins were observed (Fig. 2). Laboratory studies including muscle enzymes were unremarkable. Patients with anti–TIF1-γ juvenile dermatomyositis tend to have chronic or treatment-resistant disease course. Undermining ulcer is a severe cutaneous manifestation associated with vasculitis or vascular damage due to panniculitis or calcinosis. After 2 cycles of monthly intravenous immunoglobulin therapy (~1.7 g/kg/month) along with continuing use of prednisone and thalidomide at previous dose, the ulcers healed completely (Fig. 3), and other skin lesions improved significantly as well.FIGURE 1: Gottron sign (A) and diffuse erythematous eruption on the buttocks (B).FIGURE 2: Undermining ulcers on the left upper arm.FIGURE 3: The ulcers healed completely after 2 months of treatment.Differential diagnosis: Pyoderma gangrenosum Pressure ulcer Buruli ulcer Dermatomyositis (anti–TIF1-γ, anti-MDA5)

Abstract 10594: Cardiac Tamponade in a Covid-19 Positive Patient With Idiopathic Capillary Leak Syndrome: A Perilous Combination

Introduction: Clarkson’s disease, more known as idiopathic systemic capillary leak syndrome (SCLS) is a rare condition characterized by hypotensive episodes due to capillary hyperpermeability and can manifest as fluid accumulation in any organ or potential space. This may cause a range of complications: respiratory failure (from pulmonary edema or pleural effusion), mesenteric hypoperfusion (from hepatic congestion and severe intestinal edema), compartment syndrome and rhabdomyolysis, and even shock from hypovolemia or cardiac tamponade. Very few cases of cardiac tamponade in Clarkson's disease and COVID-19 have been reported, and when present, is certainly a serious and life-threatening complication. Case Summary: A 44-year-old female - with prior episodes of angioedema, pleural and pericardial effusions aggravated by menstruation and infection - presented with hypotension and diaphoresis. She was exposed to a COVID patient and eventually tested positive for COVID-19 infection. Persistent hypotension warranted triple inotropic support. Initial laboratories revealed hemoconcentration and hypoalbuminemia. Urinalysis was normal. 2D echocardiography showed normal left ventricular ejection fraction but with large pericardial effusion and signs of cardiac tamponade, hence, she underwent emergency pericardial windowing. She then developed pleural effusion which was drained surgically. Hepatitis, mycoplasmal and Epstein-Barr virus were negative. Direct and indirect Coomb’s test, and Lupus panel were unremarkable. Serum free light chain panel, immunopathology and C1 inhibitor results were non-diagnostic. Patient was managed as a case of idiopathic SCLS or Clarkson's disease. Methylprednisolone pulse therapy (MPPT) and intravenous immunoglobulin (IVIg) were administered. Patient was discharged with tapering doses of oral steroids and scheduled monthly IVIg infusion. Conclusions: Cardiac tamponade is a very rare but life-threatening complication of Clarkson’s disease, and on top of a COVID-19 infection, warrants emergent intervention. The pathogenesis is not yet fully elucidated. Diagnosis of SCLS is challenging thus recurrent pericardial and pleural effusions should raise the clinician’s index of suspicion.

A CASE OF PULMONARY EMBOLISM POST COVID-19 INFECTION IN A PATIENT WITH STAT3 MUTATION

<h3>Introduction</h3> Signal transducer and activator of transcription 3 (STAT3) is a transcriptional regulator that plays an important role in controlling the innate and adaptive immune system. Hyper IgE syndrome, caused by a STAT3 deficiency, is a rare disorder that commonly presents with connective tissue, skeletal, and vascular abnormalities. Known vasculopathies seen in this syndrome include aneurysms and thrombotic events frequently in coronary and cerebral vascular systems. <h3>Case Description</h3> We report a 55-year-old white male with a known STAT3 deficiency based on clinical symptomology and genetic testing. The patient has been on monthly intravenous immunoglobulin therapy. He has refused active and passive immunization to COVID-19 due to religious reasons. Soon after a COVID-19 infection he presented with dyspnea, leg swelling, and chest pain. Worsening symptoms caused him to be admitted to the hospital and a V/Q scan was performed. The result showed a pulmonary embolism of the left lower lobe, he was treated for this condition and then discharged from the hospital. <h3>Discussion</h3> STAT3 deficient patients typically present with a triad of symptoms: eosinophilia, atopic dermatitis, and pulmonary/skin infections. The complication of recurrent vasculopathies, including clots, has been seen in many patients with a STAT3 deficiency. Outside of STAT3 deficient patients, there has been multiple clinical scenarios where pulmonary embolisms have been present in patients after a COVID-19 infection. This is the first published case of a STAT3 deficient patient presenting with a pulmonary embolism due to a COVID infection.

AB010. Keloidal scleroderma with isolated intertriginous involvement

A 33-year-old African-American female with scleroderma, Raynaud phenomenon, and possible systemic lupus erythematosus (SLE) presented to dermatology clinic for evaluation of a 1-year history of slowly growing plaques in her bilateral axillae and inguinal region. The patient was initially diagnosed with scleroderma approximately five years prior to presentation following the onset of sclerodactyly, arthralgias, myalgias, and severe obstructive lung disease. Two years prior to presentation, she was started on monthly intravenous immunoglobulin infusions. Her other medications included hydroxychloroquine, mycophenolic acid, cilostazol, and amlodipine. One year ago, she began developing leathery, firm, dark plaques underneath both armpits. The plaques slowly enlarged and new plaques began forming in her inguinal region. They were nonpruritic but mildly tender. On exam, the patient had well-demarcated, linear, hyperpigmented, indurated plaques that coalesced in her bilateral axillae, bilateral inguinal folds, and bilateral peri-inguinal region with no evident secondary scale or crust. She also had sclerodactyly of the digits of her bilateral hands and blue-white discoloration of her 4th digit of the right hand. A 4 mm punch biopsy was performed from her left axilla and was consistent with keloidal morphea/scleroderma. Keloidal scleroderma, also known as nodular scleroderma, is a rare manifestation of systemic sclerosis that is usually characterized by innumerable nodules or keloidal plaques on the trunk. We present a case of isolated intertriginous keloidal scleroderma, an exceedingly uncommon distribution for this condition. A recent literature review of nodular scleroderma by Kassira et al. revealed only one reported case with lesions in intertriginous areas. Given the rarity of the diagnosis, our knowledge of efficacious treatment options remains limited. Possible options for treatment include methotrexate, ultraviolet A light therapy, and narrow-band ultraviolet B light therapy. Teaching point: the patient’s biopsy-proven isolated intertriginous keloidal scleroderma represents an uncommon clinical presentation for an already rare variant of systemic sclerosis.

IVIG in childhood primary angiitis of the central nervous system: A case report

Aggressive immunosuppressive therapies have been proposed to treat primary angiitis of the central nervous system (PACNS). Here, we report the first successfully stabilized case of childhood, small-vessel PACNS with intravenous immunoglobulin (IVIG) therapy.A 12-year-old boy was admitted to our hospital complaining of recurrent headaches and upper-left homonymous quadrantanopia, since the age of 11 years. Brain computed tomography scans revealed fine calcification in the right temporal and occipital lobes. Brain magnetic resonance imaging scans revealed white matter lesions, with gadolinium enhancement, which waxed, waned, and migrated for 1 year, without immunomodulatory therapies. A cerebrospinal fluid study showed pleocytosis (12 cells per µl). No clinical or serological findings suggested systemic inflammation or vasculitis. Brain angiography was unremarkable. Brain biopsy revealed thickened and hyalinized small vessels, with intramural infiltration of inflammatory cells, which confirmed the diagnosis of small-vessel PACNS. Because the patient developed surgical site infection following biopsy, the administration of monthly IVIG (2 g/kg) was prescribed, instead of immunosuppressive agents. After IVIG therapy, the patient remained stable, except for a single episode of mild radiological exacerbation at 16 months, which occurred when the IVIG interval was expanded. Oral prednisone was added and gradually tapered. At 50 months, his intellectual abilities and motor functions were normal, although he showed residual upper-left homonymous quadrantanopia and post-exercise headache. A temporary headache, associated with the immunoglobulin infusion, was resolved by slowing the infusion rate. PACNS should be treated aggressively to improve prognosis. However, when immunosuppressants are contraindicated, IVIG may be an alternative therapeutic option.

Autoinflammation in addition to combined immunodeficiency: SLC29A3 gene defect

IntroductionH Syndrome is an autosomal recessive (AR) disease caused by defects in SLCA29A3 gene. This gene encodes the equilibrative nucleoside transporter, the protein which is highly expressed in spleen, lymph node and bone marrow. Autoinflammation and autoimmunity accompanies H Syndrome (HS). AimThe aim was to further elucidate the mechanisms of disease by molecular studies in a patient with SLC29A3 gene defect. Patient and MethodsMitochondrial dysfunction, lysosomal integrity, cytokine response in response to stimulation with different pattern recognition receptor ligands, and circulating cell-free mitochondrial-DNA(ccf-mtDNA) level in plasma were analyzed compared to controls to understand the cellular triggers of autoinflammation. RNA sequencing (RS) analyses were also performed in monocytes before/after culture with lipopolysaccharide. ResultsPatient had progressive destructive arthropathy in addition to clinical findings due to combined immunodeficiency. Pure red cell aplasia (PRCA), vitiligo, diabetes, multiple autoantibody positivity, lymphopenia, increased acute phase reactants were present. Recent thymic emigrants (RTE), naïve T cells were decreased, effector memory CD4 + T cells, nonclassical inflammatory monocytes were increased. Patient’s peripheral blood mononuclear cells secreted more IL-1β and IL-6, showed lysosomal disruption and significant mitochondrial dysfunction compared to healthy controls. Plasma ccf-mtDNA level was significantly elevated compared to age-matched controls (p < 0.05). RNA sequencing studies revealed decreased expression of NLR Family Caspase Recrument-Domain Containing 4(NLRC4), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4(PFKFB4), serine dehydratase(SDS), heparan sulfate(Glucosamine) 3-O-sulfotransferase 1(HS3ST1), neutral cholesterol ester hydrolase 1 (NCEH1), and interleukin-8 (IL-8) in patient’s monocytes compared to controls. Longstanding PRCA, which is possibly autoimmune, resolved after initiating monthly intravenous immunoglobulins (IVIG) and low dose steroids to the patient. ConclusionAlthough autoinflammation and autoimmunity are reported in HS, by functional analyses we here show in the present patient that over-active inflammasome pathway in HS might be related with mitochondrial and lysosomal dysfunction. Increased plasma ccf-mtDNA may be used as a biomarker of inflammasomopathy in HS. HS should be included in the classification of primary immunodeficiency diseases.

Intensive Combination Immunotherapy and Neuroinflammation Resolution in a Child With Anti-PCA-1 (Yo) Paraneoplastic Syndrome and 2 Malignancies

Paraneoplastic cerebellar degeneration is rare and noteworthy in children. In this 7-year-old, it was documented to have occurred within a year of ataxia presentation. The instigating cancer was stage III adrenal adenocarcinoma, remitted after surgical resection at age 2. When her severe ataxia progressed, neuroinflammation was characterized by high cerebrospinal fluid Purkinje cell cytoplasmic antibody type 1 titers, oligoclonal bands, and neurofilament light chain. The immunotherapy strategy was to replace IV methylprednisolone, which lowered Purkinje cell cytoplasmic antibody type 1 titers without clinical improvement, with induction of adrenocorticotropic hormone/intravenous immunoglobulin/rituximab (ACTH/IVIG/rituximab) combination immunotherapy, ACTH/dexamethasone transition, and intravenous immunoglobulin maintenance. She became self-ambulatory and cerebrospinal fluid inflammatory markers regressed. Down syndrome predisposed her to a second cancer, pre-B acute lymphoblastic leukemia, 4 years later. Despite reversible cytosine arabinoside-provoked cerebellar toxicity, the ataxia is stable on monthly intravenous immunoglobulin without relapse, now 5 years after initial diagnosis. This report illustrates the use of cerebrospinal fluid biomarkers to detect, target, and monitor neuroinflammation, and successful combinations of immunotherapy to better the quality of life.

Case Report: X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency and an unusual Aspergillus infection

NEMO (NF-kB essential modulator) is a regulatory factor involved in signaling pathways of the innate and adaptative immune systems. Hypomorphic mutation of the NEMO gene (also called IKBKG gene) on the X chromosome leads to X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency. Affected male children present a developmental phenotype with hypotrichosis, hypohydrosis, and hypodontia with conical incisors and susceptibility to pyogenic bacteria, mycobacteria and viruses. Most also have impaired antibody response to polysaccharide antigens. Here we present the case of a 7-year-old boy with disseminated BCGitis and unusual Aspergillus infection who was later diagnosed with a homozygous mutation of the NEMO gene. Appropriate long term anti-mycobacterial medications, prophylactic anti-fungal therapy and current monthly intravenous immunoglobulin (IVIG) stabilized the patient’s condition and has significantly improved his general health. High incidence of atypical mycobacterial infection in such cases emphasize the need for prophylaxis. In conclusion, attention to gender, pattern of infections, and precise physical exam helped us to diagnose and appropriately manage this case. We propose prophylactic therapy for mycobacterial and opportunistic infections after the confirmation of homozygous NEMO gene mutation.

Long-term efficacy of high doses of intravenous immunoglobulins in generalized scleromyxoedema: Case report.

Scleromyxoedema is a rare disease with a progressive and disabling course involving dermal deposition of mucin and fibroblast proliferation; it is characterized clinically by a diffuse papular eruption, skin thickening, oedema and decreased skin flexibility, especially of the face and hands. Current therapy options are based on evidence from a limited number of case reports. The clinical manifestations and treatment of a 64-year-old man affected by scleromyxoedema with severe skin involvement of the face, arms and hands, decreased mouth opening and hypomotility of the fingers are reported. Dysphagia, asthenia and immunoglobulin G lambda monoclonal gammopathy were also present. Previous treatment with topical and systemic corticosteroids, psoralen plus ultraviolet A radiation therapy, plasmapheresis, extracorporeal photochemotherapy, hydroxychloroquine and cyclophosphamide had been unsuccessful. Treatment with intravenous immunoglobulins at a dosage of 2 g/kg monthly was started. Considerable improvements were observed after seven cycles of therapy, with recovery of skin elasticity, an increase in facial mimic movement, restoration of joint function and improvement in the modified Rodnan score. There were no observed side-effects. The patient remains in remission on monthly maintenance intravenous immunoglobulins, 2 years after initial treatment.

Long-term results of rituximab–intravenous immunoglobulin combination therapy in patients with epidermolysis bullosa acquisita resistant to conventional therapy

Background: Epidermolysis bullosa acquisita (EBA) is a rare subepidermal bullous disease. Long-term remission in this disease is difficult using current treatments, unlike that in patients with other autoimmune bullous diseases.Objective: We retrospectively evaluated the effectiveness and side effects of rituximab–intravenous immunoglobulin (IVIg) combination treatment in five patients with EBA resistant to conventional treatment.Patients and methods: Rituximab (375 mg/m2) was administered for four consecutive weeks to four patients, and their treatment continued with IVIg at a dose of 2 g/kg/month. One patient received two cycles of rituximab for three consecutive weeks, IVIg in the fourth week, followed by monthly IVIg administrations as in the other patients.Results: The total number of IVIg therapy cycles ranged from 10 to 26 (mean 19.4). Mean skin involvement, mucosal involvement, and disease severity scores decreased after a mean follow-up of 22.6 months (range, 10–28 months). In an analysis performed during months 24–28, the number of CD19-positive B cells was found to be below the normal reference range in four patients.Limitations: This was a retrospective study with a limited number of patients.Conclusion: Rituximab–IVIg combination treatment seems to be effective and safe for treating patients with EBA resistant to conventional treatments.

Efficacy of intravenous immunoglobulin therapy in giant cell hepatitis with autoimmune hemolytic anemia: A multicenter study

Giant cell hepatitis with autoimmune hemolytic anemia (GCH-AHA) is a rare disease of infancy, of possible autoimmune mechanism with poor prognosis due to its scarce response to immunosuppressive drugs. The aim of this retrospective multicenter study was to evaluate the efficacy and safety of intravenous immunoglobulin (IVIg) treatment in inducing and maintaining remission of the liver disease, in patients with GCH-AHA. Seven children with GCH-AHA, four newly diagnosed, and three in relapse, being treated with different therapies, received one to three IVIg infusions (0.5 to 2g/kg) in association with other immunosuppressive drugs. Subsequently five of them received monthly sequential IVIg infusions (mean 13.4, range 7-24). IVIg infusions as first-line therapy associated with prednisone and other immunosuppressive drugs significantly (P=0.04) reduced the aminotransferase activity in all patients and normalized prothrombin activity in the only patient with severe liver dysfunction. Sequential monthly IVIg infusions determined a steroid-sparing effect and allowed a complete or partial remission in all patients, although with temporary efficacy, since relapse of the hemolytic anemia and/or of liver disease occurred in all patients. IVIg infusions were associated with mild side effects in two patients. IVIg infusion can be safely and effectively administered in patients with severe GCH-AHA at diagnosis, or in case of relapse, in association with other immunosuppressive drugs. Repeated IVIg infusions may help maintain remission, however, due to their temporary efficacy, they should not be routinely employed.

Eculizumab to treat antibody-mediated rejection in a 7-year-old kidney transplant recipient.

We report on successful early eculizumab administration to treat acute antibody-mediated rejection (ABMR) in a highly sensitized kidney transplant recipient. The recipient is a 7-year-old boy who received, 6 months after a desensitization protocol with monthly intravenous immunoglobulin infusion, a second kidney transplant in the presence of low donor-specific antibodies (DSAs). Both pretransplant lymphocytotoxic and flow cytometric crossmatch were negative. Allograft function recovered promptly, with excellent initial function. On postoperative day (POD) 4, the child developed significant proteinuria with an acute rise in serum creatinine. Allograft biopsy showed severe acute ABMR. Intravenous eculizumab (600 mg), preceded by a single session of plasmapheresis, was administered on POD 5 and 12 along with a 4-day thymoglobulin course. After the first dose of eculizumab, a strikingly rapid normalization of allograft function with a decrease in proteinuria occurred. However, because circulating DSA levels remained elevated, the child received 3 doses of intravenous immunoglobulin (POD 15, 16, and 17), with a significant subsequent decrease in DSA levels. At 9 months after transplant, the child continues to maintain excellent allograft function with undetectable circulating DSA levels. This unique case highlights the potential efficacy of using early eculizumab to rapidly reverse severe ABMR in pediatric transplantation, and therefore it suggests a novel therapeutic approach to treat acute ABMR.

Common Variable Immunodeficiency and autoimmunity in two teenagers brothers in Bogotá

Event Abstract Back to Event Common Variable Immunodeficiency and autoimmunity in two teenagers brothers in Bogotá CARLOS E. OLMOS1* and CATALINA GOMEZ PARADA1 1 Cayre IPS y Fundacion, Colombia Introduction: Common variable immunodeficiency (CVID) is the primary immunodeficiency most frequently identified in the clinical practice. Clinically, it is defined as the presence of recurrent infections, reduction in IgG serum (at least 2 standard deviations before the reference values for the subject’s age), at least another one of the Ig (IgA or IgM), and a reduction or absence of the production of antibody. The clinical spectrum include multiple recurrent respiratory infections, systemic bacterial infections, gastrointestinal complications, and autoimmunity. We report two cases of CVID occurring in siblings with infectious and autoimmunity manifestations early in school age. Case report: Male adolescents from Tolima, Colombia, diagnosed with CVID after 6 years of the onset of symptoms. The first brother was diagnosed at the 12 years of age with a history of severe insulin-depend diabetes mellitus since the age of two years associated to severe respiratory infections with multiple hospital admissions including sinusitis, otitis media, and complicated pneumonias with bronchiectasis, chronic conjunctivitis, gastroenteropathy, and lymphadenopathies with hypogammaglobulinemia G and M and specific antibody deficiency. The second patient was diagnosed at the 14 years of age after a history of recurrent moderate respiratory infections and frequent diarrheal illness since the age of 6 with development of pernicious anemia, hyperparathyroidism with clinical rickets, detection of hypogammaglobulinemia G and M, and specific antibody deficiency. Both patients are being treated with monthly intravenous immunoglobulin G [IVIG] replacement, vitamin B12 and D, additional nutritional support and multidisciplinary management. Discussion: The CVID is usually a sporadic and non-monogenic condition. The presentation in two brothers with recurrent bacterial and viral infections, autoimmunity and gastroenteropathy point us to a Mendelian susceptibility. This report also demonstrates the difficulty of diagnosing early CVID based only on the traditional alert signs such as recurrent infections. Autoimmunity manifestations should alert on additional signs suggesting CVID. References • Javier Chinen, MD, PhD,a Luigi D. Notarangelo, MD,b and William T. Shearer, MD, PhDa. Advances in basic and clinical immunology in 2014 J Allergy Clin Immunol 2015;135:1132-41. • Karakoc-Aydiner E, AO Ozen, Baris S, Ercan H, Ozdemir C, Barlan IB. Alteration in Humoral Immunity Is Common Among Family Members of Patients With Common Variable Immunodeficiency. J Investig Allergol Clin Immunol 2014; Vol. 24(5): 346-351. • Xiao X, et al, Common variable immunodeficiency and autoimmunity – an inconvenient truth, Autoimmun Rev (2014). • Jolles S. The variable in common variable immunodeficiency: a disease of complex phenotypes. J Allergy Clin Immunol Pract 2013; 1:545–56. • Ochs HD. Common variable immunodeficiency (CVID): new genetic insight and unanswered questions. British Society for Immunology, Clinical and Experimental Immunology, 178: 5–6. Keywords: Common variable immunodeficiency (CVID), hypogammaglobulinemia, Autoimmunity, recurrent respiratory infections, Pernicious anemia Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015. Presentation Type: Poster Presentation Topic: Immunodeficiencies Citation: OLMOS CE and GOMEZ PARADA C (2015). Common Variable Immunodeficiency and autoimmunity in two teenagers brothers in Bogotá. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00131 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 02 Jun 2015; Published Online: 14 Sep 2015. * Correspondence: Dr. CARLOS E OLMOS, Cayre IPS y Fundacion, Bogota, Colombia, colmos.8600@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers CARLOS E OLMOS CATALINA GOMEZ PARADA Google CARLOS E OLMOS CATALINA GOMEZ PARADA Google Scholar CARLOS E OLMOS CATALINA GOMEZ PARADA PubMed CARLOS E OLMOS CATALINA GOMEZ PARADA Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Optimizing immunoglobulin G therapy in chronic autoimmune neuropathies.

Prolonged intravenous immunoglobulin (IVIg) therapy is frequently used for the treatment of chronic autoimmune neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). Recent studies of the electrophysiology and immunology of various neurological diseases, including CIDP, suggest that antibody-induced reversible dysfunction of nodes of Ranvier plays an important role in conduction block and morbidity 1. This may be more important, at least in the short term, than demyelination or axon destruction. The IVIg doses and dosing intervals are usually chosen empirically due to a paucity of data from dose-response and pharmacodynamic studies. The use of 2 g/kg as loading dose and maintenance doses of 1 g/kg every 3–4 weeks are common. European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) guidelines suggest that the dose and frequency of IVIg should be tailored to an individual patient's needs 2. However, there are no recommendations as to how this can be achieved or the outcomes upon which adjustments in therapy should be based. Clinical observations suggest that with currently used immunoglobulin (Ig) regimens the beneficial effects of each dose of IVIg may be transient, wearing off before the next cycle of treatment is required. These observations have been confirmed by case reports. A patient with CIDP repeatedly showed improvement in ankle dorsiflexion over the first 5–9 days following the administration of IVIg. The improvement was sustained for approximately 10 days but then declined, reaching pretreatment levels by the end of the month 3. These periodic fluctuations in strength were also reported in a patient with MMN on monthly IVIg therapy 4. However, this patient was switched to subcutaneous immunoglobulin (SCIg) therapy and, with a 25% increase in total monthly dose, his disease stabilized. Weekly SCIg has been investigated as a means of continuously maintaining high serum IgG levels, resulting in stabilization of neuromuscular function in CIDP and MMN patients 5–8. Significant variations in IgG metabolism have been reported among patients with CIDP 9. These differences were unrelated to the administered dose, weight, body mass index or degree of functional improvement. However, the patient-specific post-infusion rise in IgG levels, which may be dependent upon the individual rate of IgG metabolism, may explain the interpatient differences in infusion frequency requirements. The optimum dosage and frequency of IVIg infusions appears to be patient-specific 9. It has been shown that actual doses and dosing intervals vary from conventional empirical dosing, suggesting that physicians may already be adjusting doses based on the individual patient's clinical condition and treatment response 10. A prospective study has shown that CIDP patients maintain strength optimally when their IgG levels reach a plateau supported by infusions as frequent as once every 10 days. The intra- and interpatient variability in IgG may indicate that individualized constant levels of IgG facilitate achieving clinical stability 11. Overall, these studies show that many patients with CIDP have increased benefit when IVIg is administered at more frequent intervals, with 30–60% of patients showing improvement when IVIg is administered at intervals of 10–14 days or less 9–11. An ongoing study supported by CSL Behring in collaboration with AxelaCare has demonstrated that grip strength and disability measurements performed frequently by the patient at home can be reported wirelessly, collected by a database service, and reported to the physician 12. This information can prove useful for assessing the extent and duration of responses to individual IgG doses. In addition, this type of frequent data collection can be used to identify patients who would benefit from weekly SCIg rather than IVIg every 3−4 weeks and those in whom IgG therapy is ineffective. Currently, Ig replacement therapy is widely used in the treatment of chronic autoimmune neuropathies. Individualization of IgG treatment regimens may optimize efficacy and minimize disability. Further studies are needed to determine whether patient-specific regimens result in improved long-term outcomes.

Dose and outcomes in primary immunodeficiency disorders.

Currently, the principal form of treatment for patients with primary immunodeficiency disorders (PID) in Europe is subcutaneous immunoglobulin (SCIg) replacement therapy. Conversely, until relatively recently, intravenous immunoglobulin (IVIg) replacement was the preferred option for treatment of PID in the United States. Patients with PID are more susceptible to recurrent or severe infections than individuals without PID. A retrospective analysis of data from the European Society of Immunodeficiencies (ESID) registry, between 2004 and 2010, showed marked regional variability in the clinical outcomes of patients with PID receiving SCIg or IVIg replacement therapy 1. In this analysis, patients receiving IVIg appeared to present with more serious bacterial infections and spend more days in hospital than patients receiving SCIg. Furthermore, in a subgroup of patients, those who switched from IVIg to SCIg replacement therapy spent fewer days in hospital after the switch 1. However, there are a number of considerations when deciding on the route of immunoglobulin G (IgG) administration. The volume of immunoglobulin (Ig)G that can be given into the subcutaneous (s.c.) space can be limited when compared with the volume that can be delivered intravenously (i.v.); thus, SCIg must be administered more frequently than IVIg. SCIg treatment regimens include weekly, bi-weekly or daily push doses that can be self-administered. Typical regimens for the i.v. route of administration are once every 3–4 weeks given at home or in a clinic setting. In contrast to the cycle of peak and trough serum IgG levels following IVIg infusion, SCIg regimens produce minimal variation in trough serum IgG levels 2. Systemic side effects are more common with IVIg than SCIg, and infusion site reactions are more common with SCIg, particularly during the early phase of s.c. IgG replacement therapy 2,3. An alternative method to facilitate SCIg administration is a pre-infusion of recombinant hyaluronidase followed by a monthly dose of s.c. IgG. This method has been reported to have a low rate of systemic side effects, similar to conventional SCIg 4. The impact of home-based monthly IVIg and weekly SCIg self-infusions on health-related quality of life (HRQoL), treatment satisfaction and patient preference for either IgG replacement venue has been investigated in patients with PID treated previously with IVIg in the hospital or at home 5. Patients who switched from hospital-based IVIg to IVIg or SCIg self-infusions at home reported significantly fewer limitations with work/daily activities, significantly improved quality of life (e.g. feeling of more energy, less tiredness and fatigue) and better general health. While s.c. IgG were preferred over i.v. infusions by PID patients, overall patient satisfaction and preference for IgG replacement therapy was linked to home IgG therapy 5. Specifically, the effect on improving the quality of life (QoL) for PID patients was less striking in the switch from home-based IVIg to SCIg self-infusions at home; home therapy was the major factor in improving QoL 5. Administration of IgG via the s.c. route is becoming increasingly popular in the United States, and in a survey of European and US clinical immunologists the majority of respondents agreed that IgG administered s.c. is as effective as IVIg therapy 6. However, the question still remains as to the optimal dosage regimen that provides the best clinical outcome in preventing serious and/or recurrent infections in patients with PID. Progressive increments in the dose of IVIg produce linear increases in trough IgG levels, leading to a 27% decline in the incidence of pneumonia with every 100 mg/dl increase in trough IgG up to at least 1000 mg/dl 7. Similarly, higher SCIg doses have been shown to also correlate with higher serum IgG levels. However, although higher IgG serum levels achieved by SCIg infusions correlated with lower rates of non-serious infections, there was no correlation between the SCIg dose administered and the rate of infection in this study 8. Nevertheless, higher SCIg doses appeared to provide improvements in a number of clinical outcomes, including fewer days in hospital, fewer days on antibiotics and a reduced annual rate of infection 8. Although targeting a serum/trough IgG level that raises IgG levels above 500 mg/dl is a useful guide in beginning IgG replacement therapy for patients with PID 7,8, in healthy individuals there is a wide variation in serum IgG levels well above this ‘targeted’ serum IgG level 9. Furthermore, the level of serum IgG that protects patients with PID against recurrent or serious infections is likely to vary widely for each patient, as it does in healthy individuals 9. The suggested goal of therapy should be to identify the individual ‘biological’ serum IgG trough level required to maintain a PID patient as infection-free as possible 10. The ‘biological’ level can be obtained by charting a patient's serious or recurrent infections against their IgG levels over time, and is a ‘moving target’ because it can be altered by changes in clinical status, such as changes in body weight, pregnancy or the development of co-morbid conditions, such as renal 10 and gastrointestinal disease. The concept of targeting an individual PID patient's ‘biological’ IgG level is supported by data obtained by a large cohort of patients with common variable immunodeficiency (CVID) or X-linked agammaglobulinaemia (XLA) who were followed-up over a period of 22 years 11. This study clearly showed that there is a wide range of serum IgG levels that were required to keep these PID patients as infection-free as possible, and that only some PID patients need the largest doses of IgG that have been shown to reduce the development of pneumonias 7. In addition, there was variability in the amount of IgG required to keep CVID versus XLA patients healthy, suggesting that the original IgG repertoire present in CVID versus XLA patients may be important in determining the IgG dose required to keep these two different PID patient populations healthy. Moreover, the wide variation in the dose of IgG used to keep PID patients healthy did not exceed the wide range of serum levels found in healthy, age-appropriate individuals. A 5-year prospective study identified subgroups of patients with PID at high risk of infection 12. CVID patients had a high risk of pneumonia if they had low IgG and IgA levels at diagnosis or an IgA level 500 mg/dl may be required to decrease the incidence and progression of bronchiectasis in patients with XLA and CVID 13. In another 2-year prospective study, IgG trough levels >600 mg/dl were shown to be better in controlling bacterial infections and pulmonary complications in patients with CVID 14. In addition, doses of 800–>1100 mg/dl have been shown to produce a slower decline in age-associated pulmonary function tests in adults with PID 15. In conclusion, individualizing the IgG dose and route of administration, together with identification of a given PID patient's ‘biological IgG level’, helps prevent severe and recurrent infections. In addition, individualization of therapy can improve adherence and improve the QoL of PID patients by allowing each individual patient to choose the IgG replacement venue that best suits their lifestyle. Finally, the goal of IgG replacement therapy is to provide sufficient amounts of IgG, by the i.v. or s.c. route, to minimize serious and recurrent infection. This can be achieved by identifying and then maintaining each PID patient's ‘biological IgG level’ that can vary over time depending on the development of co-morbid conditions.

Use of immunoglobulin (Ig) in peripheral neuropathies. Impact of Ig on remission rates: comparison of intravenous immunoglobulin and subcutaneous immunoglobulin.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a progressive or relapsing disease with a worldwide prevalence of up to nine individuals per 100 000 1. Randomized trials suggest that corticosteroids, plasma exchange and intravenous immunoglobulin (IVIg) can temporarily reduce impairment and disability. Although approximately 60–70% of the patients respond to the initial therapy, reports on long-term experience of IVIg use in CIDP are rare. Corticosteroids, plasma exchange and IVIg are first-line treatment options in CIDP; however, a risk of long-term adverse effects is the main disadvantage of corticosteroids. Long-term plasma exchange may be less tolerated, and expense can be a concern with IVIg. Two Phase III clinical trials proved the efficacy of IVIg for long-term treatment in CIDP. The IVIg CIDP Efficacy (ICE) trial was a large study that evaluated for the first time the long-term efficacy of IVIg in 117 patients with CIDP 2. Of the 57 patients who received IVIg and were first-period or cross-over-period responders, as assessed with the adjusted inflammatory neuropathy cause and treatment (INCAT) scale, 31 were reassigned randomly to IVIg and 26 were assigned randomly to placebo. IVIg-treated patients (13%) showed a significantly lower relapse rate compared to placebo-treated patients (45%), meaning that 55% of those who were re-randomized to placebo in the extension trial did not deteriorate in a time-frame of approximately 24 weeks 2. In the Privigen Impact on Mobility and Autonomy (PRIMA) study, IVIg-pretreated and IVIg-naive CIDP patients were enrolled and treated for 21 weeks 3. Approximately 61% of the patients showed a significant improvement according to the INCAT scale. Fifty per cent of patients responded to IVIg within the first 4 weeks and 88% of patients within 10 weeks. Of the 31 screened patients, only one CIDP patient (9%) failed the IVIg dependency test and did not deteriorate in the wash-out phase 3. Recently, a retrospective study aimed to evaluate the long-term outcomes in 86 CIDP patients treated with IVIg 4. Data were collected at four time-points: baseline (prior to the start of IVIg treatment); at short-term visit (approximately 6 weeks after IVIg initiation); at mid-term visit (approximately 24 weeks after IVIg); and at last follow-up visit (more than 48 weeks after initiating IVIg treatment). At the mid-term visit, 31 patients had only one IVIg course throughout the entire observation period. Twenty CIDP patients did not receive IVIg at all. Of these 20 patients, 12 were stable. At the long-term visit, 22 patients (25·6%) showed no signs of deterioration 4. There are limited data available on the long-term treatment of CIDP and multifocal motor neuropathy (MMN) with subcutaneous immunoglobulin (SCIg). In a recent report, two patients with atypical CIDP (multifocal acquired demyelinating sensory and motor neuropathy – MADSAM), were treated with SCIg over a time-period of 46 months 5. The Medical Research Council (MRC) sum score remained stable during the entire time-period. In a randomized Phase II study, 30 CIDP patients were enrolled and randomized to placebo and SCIg 6. The treatment period was 12 weeks, with twice- or thrice-weekly SCIg injections (30–300 ml/week; 4·8–48 g/week). After 12 weeks, significant increases (P > 0·05) in isokinetic muscle strength were observed in SCIg-treated patients (5·5 ± 9·5%) compared to the decline observed in the placebo group (14·4 ± 20·3%) 6. Two small case series investigated the effect of SCIg in MMN 7,8. SCIg proved its effectiveness in MMN in short- 7 and long-term use 8. It should be noted that the initial SCIg dose should be 100% equivalent to the monthly IVIg dose 7. A Phase III study proving the efficacy of SCIg in treating CIDP (PATH-Study) is still ongoing (ClinicalTrials.gov identifier: NCT01545076). More recently, a cost-effectiveness study comparing IVIg and SCIg was performed in Italy. Assuming that approximately 2100 CIDP patients exist in Italy, and 50% of those patients were prescribed SCIg, the estimated cost-saving in their model was approximately €1·4 million for the health-care sector 9. However, it should be noted that the cost of SCIg differs within Europe. In conclusion, both IVIg and SCIg are safe and well tolerated for long-term treatment in CIDP and MMN. The most common side effects are headaches (IVIg) and local skin reactions (SCIg). Although not very common, haemolysis is a severe side effect seen with IVIg that can potentially lead to hospitalization, especially when higher doses are administered (2 g/kg body weight).

Effective dosing strategies for therapeutic immunoglobulin: managing wear-off effects in antibody replacement to immunomodulation.

Determining optimal dosing strategies for therapeutic immunoglobulin (Ig) to minimize ‘wear-off’ effects (defined here as end-of-cycle loss of efficacy, although wear-off may also refer to secondary end-points such as fatigue) is particularly challenging in the face of limited data. Loss of efficacy of Ig therapy is linked to waning bioavailability and may be explained on the basis of Ig pharmacokinetics and catabolism. It is predominantly a problem with intravenous immunoglobulin (IVIg) as replacement therapy or as an immunomodulator. However, there are no systematic data on the scale of the problem. When Ig is used as antibody replacement therapy, the frequency of infections and trough/steady state IgG levels could be considered as surrogate markers for wear-off effects. A clear inverse relationship between trough/steady state IgG levels and pneumonia has been shown in studies of patients with primary immunodeficiency disease (PID) treated with either intravenous or subcutaneous Ig 1,2. A 27% decrease in the incidence of pneumonia for every 100 mg/dl increase in IgG trough level was reported by a meta-analysis of 17 clinical studies of patients on IVIg replacement therapy 1. Although no given IgG trough level is necessarily adequate for all patients, maintaining higher IgG levels may be beneficial 2. However, even with the use of recommended doses and achievement of Ig trough levels within the reference range, overall lung function has been shown to decline. In addition, despite adequate Ig replacement, silent and asymptomatic progression of pulmonary changes has been shown to occur in patients with primary hypogammaglobulinaemia 3. A prospective study of patients with common variable immunodeficiency disorders (CVIDs) or X-linked agammaglobulinaemia (XLA), carried out over a period of 22 years in our department, showed that a wide range of trough Ig levels was required to keep patients infection-free 4. Therefore, the goal of replacement therapy should be to improve clinical outcome and not to reach a particular IgG trough level 4. Data from a national online registry of PID in the United Kingdom (UKPID Registry) has shown that the annual incidence of new infections is approximately one patient per year 5. In patients with PID receiving IVIg the frequency of infection varies by week, with the highest frequency of infections at the end of 3- or 4-week dosing cycles, which may be indicative of a ‘wear-off’ effect 6. Whether this effect is clinically significant is debatable. Although trough Ig levels have been shown to be a reasonable marker of infection protection, trying to capture wear-off effects is challenging; there is no direct relationship between dose of Ig and infection protection once a certain critical trough IgG level has been reached. The use of trough serum IgG within the reference range as a therapeutic target has been complemented by studies supporting the concept of individualized dosing as providing optimal protection against infections 7. As these principles are increasingly translated into clinical practice and patients receive better protection, it is probable that the scale of significant wear-off effects in patients receiving Ig for antibody replacement is likely to be limited. In contrast, the serendipitous discovery of the use of Ig as an immunomodulator has meant that initial dosing strategies for the treatment of autoimmune disease were set empirically at 2 g/kg. In patients receiving IVIg for autoimmune neuropathies, end-of-cycle wear-off effects in the form of worsening weakness, paresthaesia and fatigue are well recognized clinically. In individual patients, serial measurement of muscle strength has enabled neurological ‘wear-off’ effects to be quantified. The strength of ankle dorsiflexion in a patient with chronic inflammatory demyelinating polyneuropathy (CIDP) improved following the administration IVIg reaching a peak around day 10 and then declined to pretreatment level 8. A similar fluctuation in muscle strength has been shown in a patient with multifocal motor neuropathy (MMN) during monthly IVIg 9. This clear cyclical wear-off effect can be avoided following transition to a weekly regimen of subcutaneous immunoglobulin (SCIg) administration without deterioration and with a sustained overall improvement in health-related quality of life 10. Similarly, a retrospective chart review of a cohort of patients (n = 43) with autoimmune neuropathy (MMN, n = 26; CIDP, n = 8; other, n = 9) has shown that definite wear-off effects were observed more commonly in patients receiving IVIg compared with SCIg therapy (11 versus 3; unpublished data, Table 1). Clinically stable patients treated with IVIg have low intra- and interpatient variability in IgG levels, which may indicate that constant levels are required for this stability 11. Does this imply that patients with fluctuating IgG levels have suboptimally controlled disease? Data from a randomized controlled trial suggest that patients with CIDP have stable disease on monthly doses of 1 g/kg 12. However, observational studies document a wide range of doses and treatment intervals, including 0·19–1·15 g/kg every 2–17 weeks 13 and 0·8–1·8 g/kg every 1–13 weeks 14, suggesting substantial disease heterogeneity and variation in the extent of wear-off effects. Table 1 Extent of wear-off effects in an Oxford cohort of autoimmune neuropathy patients receiving immunoglobulin (Ig) therapy In the absence of systematic data on the magnitude of ‘wear-off’ effects, Ig dosing is still tinged with empiricism. Where Ig is used as replacement therapy, the increasing acceptance of individualized dosing regimens may make accurate quantification of ‘wear-off’ effects challenging. In contrast, the emerging evidence attesting to SCIg being as equally efficacious maintenance therapy as IVIg in autoimmune neuropathies has led to its increasing adoption as an effective method of minimizing wear-off effects in this group. Data from prospective comparative trials of IVIg versus SCIg will be required to confirm this clinical impression.