Long-term efficacy of immunoglobulins in small fiber neuropathy related to Sjögren's syndrome.

The most common peripheral nervous system manifestations in Sjogren's syndrome are small fiber sensory neuropathies (SFPN) and axonal sensorimotor polyneuropathies. Currently, treatment in small fiber neuropathy is mainly symptomatic and based on anti-depressors and anti-epileptics. The benefit of treatment with polyvalent immunoglobulins for SFPN has been reported in small series of patients, although transient in several cases. The medium-to-long-term effects of polyvalent immunoglobulins (Ig) in SFPN in patients with Sjogren's syndrome who are refractory to conventional treatments remain an unmet medical need. We present our experience related to the persistent improvement of Ig in a case series of SFPN in Sjogren's syndrome and relevant data in the literature regarding the benefits of immunoglobulins, for this indication.

Recovering autonomy is a key advantage of home-based immunoglobulin therapy in patients with myositis: A qualitative research study.

Immunoglobulins are 2nd or 3rd-line treatments in dermatomyositis (DM) or polymyositis (PM) refractory to high-dose corticosteroids and immunosuppressants. Immunoglobulins (2 g/kg/mo) are usually administered intravenously (IVIg) once a month and the patients stay at hospital for a few days. Recently, subcutaneous injections (SCIg) were proposed 2 to 3 times per week, in some dysimmune diseases. SCIg are administered at home preferably by the patient or by a nurse. We investigated the needs and attitudes of DM and PM patients with experience of IVIg and SCIg.Seven patients (6 PM and 1 DM) from a single center participated in a focus group (N = 6) or underwent in-depth interview (N = 1). Six had the experience of both IVIg at hospital and SCIg at home; 1 has received only IVIg at hospital. Verbatim was recorded and transcribed for further content analysis and computer-aided textual analysis.Clinical profiles and stories were heterogeneous. At diagnosis, muscle weakness, severe pain, and fatigue were at the forefront of patients' complaints impairing daily life. Patients reported considerable improvement with immunoglobulins. SCIg were described as easy, less disruptive for daily life, well tolerated, and less time-consuming. SCIg self-administration at home restored the feeling of autonomy and control.Interviews of DM and PM patients revealed that recovering autonomy and control was a central advantage of home-based SCIg that were efficient, well tolerated, and perceived as a good compromise between treatment burden and efficacy.

The use of octagam and gammanorm in immunodeficiency associated with hematological malignancies: a prospective study from 21 French hematology departments.

OBJECTIVE: Immunoglobulin replacement therapy (IgRT) is increasingly used in secondary immunodeficiency (SID) related to hematological malignancies (HM) to prevent infections. Study's objective was to document prospectively the efficacy and safety of IgRT in patients with HM-associated SID. METHODS: Non-interventional, prospective French longitudinal study. RESULTS: One-hundred and sixty patients starting IgRT for HM-associated SID (myeloma: 54 cases, chronic lymphoid leukemia: 54, aggressive non-Hodgkin B-cell lymphoma: 19, indolent non-Hodgkin B-cell lymphoma: 29, and Hodgkin disease: 4. entered an observational, prospective, longitudinal study and were followed-up for 8.7 ± 4.0 months. Seventeen patients died (five within the context of sepsis). Compared to baseline, IgRT increased serum immunoglobulin levels by 3.4 ± 2.4 g/L and decreased frequency and severity of infections. Treatment was discontinued in 9% of patients, stopped for futility in 31%, temporally interrupted in 8%, suspended during summertime in 14% and pursued without interruption in 38% of patients. CONCLUSION: Our data confirm the efficacy of IgRT in reducing the risk of infections in HM-associated SID therefore fulfilling physicians' main expectations. They also illustrate the heterogeneity of management policies within the community setting.

Assessment of renal function in patients with myositis and treated with subcutaneous immunoglobulin: a series of 24 cases.

Immunoglobulin (Ig) therapy is used to treat a wide range of immunodeficiencies and autoimmune diseases; While, its clinical benefit has been demonstrated in several studies, Ig therapy is associated with a risk of systemic adverse effects. As such, Onset of renal impairment, including acute renal failure, osmotic nephrosis and renal insufficiency, after immunoglobulin administration is rare, but is one of the most significant concerns related to intravenous Ig use at immunomodulatory doses. However, only few studies have investigated the safety of subcutaneous Ig (SCIg) in relation to these rare conditions. The aim of this prospective study is to describe the safety of SCIg (Gammanorm), specifically with regards to renal function, in inflammatory myopathies including mainly polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM). Twenty-four cases were included: 10 patients with PM, 6 with IBM, 5 with DM, 2 with mixed connective-tissue disease (MCTD) and 1 patient with scleromyositis. SCIg was given two to three times per week at 2 g/kg/month in all patients. Patients were treated for a mean duration of 24.6 ± 11.4 months (range 8-37 months) and received a median of 78 SCIg infusions. Renal function was stable over the study period in all patients. High-dose SCIg was well tolerated; the treatment was not withdrawn during the first year in any patient for safety issues. These results suggest that the use of high-dose SCIg is generally feasible and safe in patients with inflammatory myopathies.

Efficacy and patient satisfaction in the use of subcutaneous immunoglobulin immunotherapy for the treatment of auto-immune neuromuscular diseases.

We reviewed the efficacy of SCIg administration in terms of muscle strength maintenance and patient satisfaction comparing with IVIg in the treatment of auto-immune neuromuscular diseases. A systematic review was conducted, and identified studies from databases (PUBMED, EMBASE, EBSCO, Web of Science and Google Scholar) which were analyzed. The methodological quality of the selected publications was evaluated using the Newcastle-Ottawa Scale. Data were extracted from a total of 11 studies Fixed and random-effect model meta-analyses were performed. For the maintenance of muscle strength, Overall Neuropathy Limitations Scale (ONLS) data from 100 patients diagnosed with multifocal mononeuropathy (MMN) or chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) were pooled together. Switching to subcutaneous immunoglobulin administration led to a significant improvement (fixed effects model, p = 0.002). In data collected using the Medical Research Council Scale for Muscle Strength data from 140 patients with a wider range of disorders, a small but significant improvement in overall strength was observed in the SCIg group (p < 0.0001). In addition, the results of two studies measuring health-related quality of life and patient satisfaction were pooled. Data from 49 patients suffering from MMN, CIDP, and a variety of different myopathies demonstrated a small but significant increase in the mean 36-Item Short Form Survey (SF-36) scores (p < 0.0001). A highly significant difference was revealed when comparing data from 119 patients' responses to the Life Quality Index questionnaire (LQI) assessing patient satisfaction (p < 0.0001). This is the first analysis showing that SCIg is more effective than IVIg in improving Patient Reported Outcomes in auto-immune neuromuscular disease. These results should permit a broad range of patients to self-administer immunoglobulin treatments at home, potentially improving patient acceptability while reducing hospital visits and healthcare costs for the treatment of chronic auto-immune neuropathies.

Rapid Push vs Pump-Infused Subcutaneous Immunoglobulin Treatment: a Randomized Crossover Study of Quality of Life in Primary Immunodeficiency Patients.

PURPOSE: Subcutaneous immunoglobulin replacement therapy (IgRT) may be administered once a week with a pump or every other day with a syringe (rapid push). The objective of the study was to compare the impact of pump and rapid push infusions on patient's life quality index (LQI). METHODS: This study was a randomized, crossover, multicenter, non-inferiority trial conducted in adults with primary immunodeficiency (PID) accustomed to weekly infusions at home by pump. Patients used pump or rapid push for 3 months each according to the randomized sequence. Main criterion was PID-LQI factor I (treatment interference). Non-inferiority ratio was set at 90%. RESULTS: Thirty patients entered the study; 28 completed the two periods. IgRT exposure was similar during each period. At the end of each period, mean LQI factor 1 was 87.0 (IC95% [80.3; 94.3]) and 77.80 (IC95% [71.5; 84.7]) for pump and rapid push, respectively. There was a slightly larger effect of rapid push on treatment interference than with pump so that the primary endpoint could not be met. No difference was found on other LQI components, satisfaction (TSQM), or quality of life (SF36v2). Eight patients declared to prefer rapid push while 19 others preferred pump. Of rapid push infusions, 67.2% led to local reactions vs 71.8% of pump infusions (p = 0.11) illustrating its good tolerance. Rapid push and pump infusions achieved similar trough IgG levels with similar incidence of infections. Rapid push saved 70% of administration cost when compared to pump. CONCLUSIONS: Since IgRT is a lifelong treatment in PID patients, individualization of treatment is of paramount importance. Rapid push is a new administration method in the physician's armamentarium which is preferred by some patients and is cost-effective. CLINICALTRIALS. GOV IDENTIFIER: NCT02180763 CLINICAL IMPLICATIONS: Self-administration of small volumes of immunoglobulins at home, every other day, using a syringe (rapid push) is a cost-effective alternative to administration of larger volumes by pump once a week. This study compared subcutaneous infusions of immunoglobulins either weekly via a pump or every other day via a syringe (rapid push). Rapid push is preferred by some patients and is cost-effective, therefore completing a physician's armamentarium.

A French observational study describing the use of human polyvalent immunoglobulins in hematological malignancy-associated secondary immunodeficiency.

OBJECTIVE: To describe the characteristics of patients suffering from secondary immunodeficiencies (SID) associated with hematological malignancies (HM), who started immunoglobulin replacement therapy (IgRT), physicians' expectations regarding IgRT, and IgRT modalities. METHODS: Non-interventional, prospective French cross-sectional study. RESULTS: The analysis included 231 patients (66 ± 12 years old) suffering from multiple myeloma (MM) (N = 64), chronic lymphoid leukemia (CLL) (N = 84), aggressive non-Hodgkin B-cell lymphoma (aNHL) (N = 32), indolent NHL (N = 39), acute leukemia (N = 6), and Hodgkin disease (N = 6). Of the HM, 47% were currently treated, 42% were relapsing or refractory, 23% of patients had received an autologous hematopoietic stem-cell transplant, and 1% had received an allograft. Serum immunoglobulin trough levels in 195 individuals were less than 5 g/L in 68.7% of cases. Most patients had a history of recurrent infections. Immunoglobulin dose was about 400 mg/kg/mo. Half of patients started with subcutaneous infusion. When starting IgRT, physicians mainly expected to prevent severe and moderate infections. They also anticipated improvement in quality of life and survival which is beyond evidence-based medicine. CONCLUSION: NHL is a frequent condition motivating IgRT besides well-recognized indications. Physicians mainly based the decision of starting IgRT on hypogammaglobulinemia and recurrence of infections but, irrespective of current recommendations, were also prepared to start IgRT prophylactically even in the absence of a history of infections.

In-depth interviews of patients with primary immunodeficiency who have experienced pump and rapid push subcutaneous infusions of immunoglobulins reveal new insights on their preference and expectations.

PURPOSE: Patients with primary immunodeficiency (PID) often receive immunoglobulin replacement therapy (IgRT). Physicians and patients have the choice between various methods of administration. For subcutaneous immunoglobulin infusions, patients may use an automated pump (P) or push the plunger of a syringe (rapid push [RP]). P infusions are performed once a week and last around 1 hour. RP decreases the duration of administration, but requires more frequent infusions. PATIENTS AND METHODS: Eight out of 30 patients (coming from a single center) who had participated in the cross-over, randomized, open-label trial comparing P and RP participated in a focus group or underwent in-depth interviews. Patients had a long history of home-based subcutaneous immunoglobulin using P. The trial suggested that RP had slightly greater interference on daily life than P, but similar efficacy and better cost-effectiveness. When asked about the delivery method they had preferred, around one-third of patients pointed out RP rather than P. In-depth interviews may reveal unforeseen reasons for patients' preferences. RESULTS: Interviews underlined the complexity of the relationship that the patients maintain with their disease and IgRT. Even if they recognized the genetic nature of the disease and claimed PID was a part of them, patients tried not to be overwhelmed by the disease. IgRT by P was well integrated in patients' routine. By contrast, RP too frequently reminded the patients of their disease. In addition, some patients pointed out the difficulty of pushing the plunger due to the viscosity of the product. Coming back too frequently, RP was not perceived as time saving over a week. Long-lasting use of P could partly explain patients' reasonable reluctance to change to RP. CONCLUSION: In-depth interviews of PID patients highlighted unforeseen reasons for patients' preference that the physician needs to explore during the shared medical decision-making process.

Subcutaneous immunoglobulins for the treatment of a patient with antisynthetase syndrome and secondary chronic immunodeficiency after anti-CD20 treatment: a case report.

BACKGROUND: Antisynthetase syndrome is a rare and debilitating multiorgan disease characterized by inflammatory myopathy, interstitial lung disease, cutaneous involvement, and frequent chronic inflammation of the joints. Standard treatments include corticosteroids and immunosuppressants. In some cases, treatment resistance may develop. Administration of immunoglobulins intravenously is recommended in patients with drug-resistant antisynthetase syndrome. CASE PRESENTATION: Here, we describe the case of a 56-year-old woman of Algerian origin. She is the first case of a patient with multidrug-resistant antisynthetase syndrome featuring pulmonary involvement and arthropathy, and chronic secondary immune deficiency with recurrent infections, after anti-CD20 treatment, in which her primary antisynthetase syndrome-related symptoms and secondary immune deficiency were treated successfully with subcutaneous administration of immunoglobulin. The administration of immunoglobulin subcutaneously was introduced at a dose of 2 g/kg per month and was well tolerated. Clinical improvement was observed within 3 months of initiation of subcutaneous administration of immunoglobulin. After 22 months of treatment, she showed a significant improvement in terms of muscle strength, pulmonary involvement, arthralgia, and immunodeficiency. Her serum creatine phosphokinase and C-reactive protein levels remained normal. Finally, she was compliant and entirely satisfied with the treatment. CONCLUSIONS: Taken together, these observations suggest that administration of immunoglobulin subcutaneously may be a useful therapeutic approach to tackle steroid-refractory antisynthetase syndrome while ensuring minimal side effects and improved treatment compliance. This treatment also allowed, in our case, for the regression of the chronic immunodeficiency secondary to rituximab treatment.

B Cell Homeostasis and Functional Properties Are Altered in an Hypochlorous Acid-Induced Murine Model of Systemic Sclerosis.

INTRODUCTION: During systemic sclerosis (SSc), peripheral B cells display alterations in subset homeostasis and functional properties and are a promising therapeutic target. However, there is only few data regarding whether these anomalies are accurately reproduced in animal models of SSc. OBJECTIVE: In this work, we assessed the B cell homeostasis modifications in an experimental model of SSc [hypochlorous acid (HOCl)-induced mouse], both at a phenotypic and functional level, during the course of the disease. METHODS: Balb/c mice underwent daily intradermal injections of HOCl (or phosphate-buffered saline) and were then sacrificed at day 21 (early inflammatory stage) or day 42 (late fibrotic stage). For phenotypic studies, the distribution of the main spleen cell subsets (B cells, T CD4 and CD8 cells, NK cells, macrophages) and splenic B cell subsets (immature, mature naïve, germinal center, antibody-secreting, memory, B1) was assessed by flow cytometry. For functional studies, splenic B cells were immediately MACS-sorted. Production of interleukin (IL)-6, CCL3, IL-10, and transforming growth factor (TGF)-ß was assessed ex vivo by RT-PCR and after 48 h of culture by ELISA. Regulatory B cell (Breg) counts were quantified by flow cytometry. RESULTS: Phenotypic analyses showed an early expansion of transitional B cells, followed by a late expansion of the mature naive subset and decrease in plasmablasts and memory B cells. These anomalies are similar to those encountered in SSc patients. Functional analyses revealed a B-cell overproduction of pro-inflammatory cytokines (IL-6 and CCL3) and an impairment of their anti-inflammatory capacities (decreased production of IL-10 and TGF-ß, reduced levels of Bregs) at the early inflammatory stage; and an overproduction of pro-fibrotic cytokines (TGF-ß and IL-6) at the late fibrotic stage. These results approximate the anomalies observed in human SSc. CONCLUSION: This work reports the existence of anomalies in B cell homeostasis and functional properties in an animal model of SSc that approximate those displayed by SSc patients. These anomalies vary over the course of the disease, which pleads for their participation in inflammatory and fibrotic events. This makes the HOCl mouse a relevant experimental model for the study of B cells, and therefore, B-cell-targeted therapies in SSc.

Management of adverse events in the treatment of patients with immunoglobulin therapy: A review of evidence.

Immunoglobulin (IG) therapy is actually used for a broad range of diseases including primary and secondary immunodeficiency disorders, and autoimmune diseases. This therapy is available for intravenous (IV) and subcutaneous (SC) administration. The efficacy of the IG therapy has been demonstrated in numerous studies and across different diseases. Generally, IG infusions are well tolerated; however some well-known adverse reactions, ranging from mild to severe, are associated with the therapy. The most common adverse reactions including headache, nausea, myalgia, fever, chills, chest discomfort, skin and anaphylactic reactions, could arise immediately during or after the infusion. Delayed events could be more severe and include migraine headaches, aseptic meningitis, haemolysis renal impairment and thrombotic events. This paper reviews all the potential adverse events related to IG therapy and establishes a comprehensive guideline for the management of these events. Moreover it resumes the opinions and clinical experience of expert endorsers on the utilization of the treatment. Published data were classified into levels of evidence and the strength of the recommendation was given for each intervention according to the GRADE system.

Long-term subcutaneous immunoglobulin use in inflammatory myopathies: A retrospective review of 19 cases.

Subcutaneous immunoglobulin (SCIg) therapy is indicated in primary and secondary immunodeficiency diseases. Its use in practice is being extended to autoimmune diseases. Few studies investigated the feasibility and safety of SCIg in these rare conditions. The aim was to describe the use of SCIg in inflammatory myopathies including polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM), in real-life settings. This case series was based upon a retrospective data collection. The primary objective was to assess the feasibility of the SCIg injections for the treatment of autoimmune diseases and adherence to high doses. Secondary objectives included safety and efficacy. Nineteen cases were identified: 7 patients were diagnosed with PM, 7 with IBM, 2 with DM, and 3 with myositis associated with connective tissue disease. Patients were treated and followed-up for a mean duration of 18.8 months (range 4.5-42). They received a median of 64 SCIg infusions and a total of 1215 infusions. Out of 14 patients, 10 showed an improvement in muscle strength, and 7 out of 11 showed an improvement in muscle disability scale. Two patients were lost to follow-up. Few slight adverse reactions were reported including mainly mild headaches and local skin reactions. Any serious adverse event was reported. These results suggest that the use of high-dose SCIg is feasible, beneficial and safe in patients with inflammatory myopathies. SCIg could be an alternative of IVIg in patients with difficult venous access or with insufficient response, and in patients preferring home care setting.

Subcutaneous Immunoglobulin Use in Inclusion Body Myositis: A Review of 6 Cases.

INTRODUCTION: Inclusion body myositis (IBM) is a slowly progressive degenerative inflammatory disorder affecting both proximal and distal muscles. Immunosuppressive therapies are generally ineffective in the treatment of this disorder, and most patients are resistant to steroid therapy. Some benefits with mild improvement were observed with intravenous immunoglobulin (IVIg), particularly in patients with severe dysphagia. OBJECTIVES: The objective of this review was to describe the use of subcutaneous Ig (SCIg) in patients with IBM and to assess its feasibility. RESULTS: This report reviews 6 cases of IBM treated with SCIg in clinical practice. All patients had received prior treatments for IBM, including immunosuppressive agents and IVIg. SCIg was administered over a long period of time, ranging from 4.5 to 27 months. No patient discontinued the SCIg because of a treatment-related event or safety issues. The 6 cases showed an improvement in muscle strength and resolution of dysphagia. For 2 patients, this improvement persisted for approximately 12 months. CONCLUSIONS: SCIg might be proposed as an alternative therapy to patients with IBM who are resistant to corticoids and immunosuppressive therapies. Our findings suggest that treatment with SCIg (Gammanorm 16.5%, Octapharma AB) is feasible and safe in patients with IBM.

Corrigendum to "high-dose subcutaneous immunoglobulins for the treatment of severe treatment-resistant polymyositis".

[This corrects the article DOI: 10.1155/2014/458231.].

Reversal of Vitamin K Antagonist (VKA) effect in patients with severe bleeding: a French multicenter observational study (Optiplex) assessing the use of Prothrombin Complex Concentrate (PCC) in current clinical practice.

INTRODUCTION: Prothrombin Complex Concentrate (PCC) is a key treatment in the management of bleeding related to Vitamin K antagonists (VKA). This study aimed to evaluate prospectively PCC use in patients with VKA-related bleeding in view of the French guidelines published in 2008. METHODS: All consecutive patients with VKA-related bleeding treated with a 4-factor PCC (Octaplex®) were selected in 33 French hospitals. Collected data included demographics, site and severity of bleeding, modalities of PCC administration, International Normalized Ratio (INR) values before and after PCC administration, outcomes and survival rate 15 days after infusion. RESULTS: Of 825 patients who received PCC between August 2008 and December 2010, 646 had severe bleeding. The main haemorrhage sites were intracranial (43.7%) and abdominal (24.3%). Mean INR before PCC was 4.4 ± 1.9; INR was unavailable in 12.5% of patients. The proportions of patients who received a PCC dose according to guidelines were 15.8% in patients with initial INR 2-2.5, 41.5% in patients with INR 2.5-3, 40.8% in patients with INR 3-3.5, 26.9% in patients with INR > 3.5, and 63.5% of patients with unknown INR. Vitamin K was administered in 84.7% of patients. The infused dose of PCC did not vary with initial INR; the mean dose was 25.3 ± 9.8 IU/Kg. Rates of controlled bleeding and target INR achievement were similar, regardless of whether or not patients were receiving PCC doses as per the guidelines. No differences in INR after PCC treatment were observed, regardless of whether or not vitamin K was administered. INR was first monitored after a mean time frame of 4.5 ± 5.6 hours post PCC. The overall survival rate at 15 days after PCC infusion was 75.4% (65.1% in patients with intracranial haemorrhage). A better prognosis was observed in patients reaching the target INR. CONCLUSIONS: Severe bleeding related to VKA needs to be better managed, particularly regarding the PCC infused dose, INR monitoring and administration of vitamin K. A dose of 25 IU/kg PCC appears to be efficacious in achieving a target INR of 1.5. Further studies are required to assess whether adjusting PCC dose and/or better management of INR would improve outcomes.