Long-term therapy with intravenous immunoglobulin is beneficial in patients with autoimmune diseases

The objective of our study is to evaluate the clinical response, steroid-sparing and adverse affects of long-term intravenous immunoglobulin (IVIG) treatment for autoimmune diseases. Patients were recruited from the Rheumatology clinic. All patients fulfilled the ACR criteria for the appropriate autoimmune disease. Beneficial effects of IVIG therapy in systemic lupus erythematosus (SLE) patients were evaluated utilizing the SLEDAI score. Clinical remission in patients with other autoimmune diseases was evaluated by a rheumatologist. Data were retrieved retrospectively from an IVIG database (Excel program). Seventeen patients—SLE (n = 11) and other autoimmune diseases (n = 6)—received a high dose IVIG protocol monthly for 6 months, followed by therapy every 2–3 months. The patients received a mean of 7.9 courses/patient. The mean follow-up for long-term therapy was 30 months. The response to IVIG treatment was remission in 12 patients. Change in the SLEDAI score following IVIG therapy was significant (p < 0.05). In responders, IVIG harbored a significant steroid-sparing effect (p < 0.05). Mild and transient adverse effects persisted with long-term therapy in 50% of patients. Severe adverse effects (pulmonary embolism and seizures) occurred early in two patients with SLE and secondary anti-phospholipid syndrome. Long-term IVIG therapy is beneficial and carries a good safety profile for SLE and other autoimmune diseases.     

High-dose intravenous immunoglobulins: an option in the treatment of systemic lupus erythematosus

Despite encouraging reports on the efficacy of intravenous immunoglobulin (IVIG) therapy in systemic lupus erythematosus (SLE), the clinical value of this treatment is not well established, and most of the data are based on case reports and small series of patients. IVIG has been used successfully to treat SLE patients with a broad spectrum of clinical manifestations, such as refractory thrombocytopenia, pancytopenia, central nervous system (CNS) involvement, secondary antiphospholipid syndrome, and lupus nephritis. The beneficial effects of IVIG on overall disease activity are usually prompt, with marked improvement within a few days, but they are often of limited duration. Improvement lasts for several weeks after the last infusion, although clinical response could be maintained by continuous monthly IVIG infusions. IVIG therapy immunomodulates autoimmune diseases by interacting with various Fcgamma receptors in such a way that it downregulates activating FcRIIA and FcRIIC and/or upregulates inhibitory FcRIIB. However, in SLE, additional mechanisms include inhibition of complement-mediated damage, modulation of production of cytokines and cytokine antagonists, modulation of T- and B-lymphocyte function, induction of apoptosis in lymphocytes and monocytes, downregulation of autoantibody production, manipulation of the idiotypic network, and neutralization of pathogenic autoantibodies. At present, IVIG in SLE is indicated either in severe cases that are nonresponsive to other therapeutic modalities, or when SLE can be controlled only with high-dose steroids; in such patients, IVIG thus becomes a useful steroid-sparing agent. However, this needs to be confirmed in double-blind, placebo-controlled studies.     

Intravenous Immunoglobulin in Lupus Panniculitis

Systemic lupus erythematosus (SLE) is a disease of unknown cause that may involve one or many organ or systems. Skin involvement is a major feature in this disease, and a wide variety of skin conditions may be present. Lupus erythematosus panniculitis (LEP) constitutes a rare form of cutaneous lupus characterized by recurrent nodular or plaque lesions that can vary from a benign and mild course to a more disfiguring disease. Initial therapy includes corticosteroids, antimalarials, and azathioprine and, in refractory cases, two antimalarials in association, mycophenolate mofetil, or other immunomodulators. Intravenous immuglobulin (IVIG) is used in many autoimmune disorders, like in SLE, although clinical trials have not yet taken place. In this report, we review skin manifestations of SLE and their treatment, IVIG, and finally a case of LEP successfully treated with IVIG when other therapy modalities failed.     

Quality of life in common variable immunodeficiency requiring intravenous immunoglobulin therapy.

BACKGROUND: There are no studies of patients with primary immunodeficiency states receiving intravenous immunoglobulin (IVIG) therapy that assess health-related quality of life (HRQOL) using a well-standardized and reproducible method. OBJECTIVES: To determine the HRQOL of patients with common variable immunodeficiency (CVID) requiring IVIG therapy, to compare these patients with patients with diabetes mellitus (DM) and congestive heart failure (CHF), to determine the factors that affect HRQOL, and to develop normative data on the HRQOL of these CVID patients, which can be used to follow the effects of future therapies. METHODS: Fifty-eight adults with CVID receiving IVIG therapy completed the Medical Outcomes Study 36-Item Short-Form Health Survey to evaluate their HRQOL and were compared with DM and CHF patients. The impact of demographic, socioeconomic, and disease-related variables and comorbid conditions was examined in the CVID population. RESULTS: Patients with CVID had lower HRQOL scores in all dimensions compared with patients with DM and in 4 of 8 dimensions compared with patients with CHF. Increasing age and female sex were negatively associated with certain aspects of HRQOL. There were no significant effects from other socioeconomic or disease-related variables or comorbid conditions examined. CONCLUSIONS: Patients with CVID receiving IVIG therapy have a significantly worse HRQOL than patients with other chronic illnesses, indicating there is much room for improvement in future therapies for this primary immunodeficiency state. The effects of future therapies can be evaluated by comparison with the normative data developed in this study.     

Intravenous immunoglobulin prevents experimental autoimmune myositis in SJL mice by reducing anti-myosin antibody and by blocking complement deposition.

High-dose intravenous immunoglobulin (IVIG) therapy has been effective in many autoimmune and systemic inflammatory diseases including polymyositis (PM) and dermatomyositis (DM). In the present study we evaluated the efficacy of IVIG using experimental models of PM and DM. An experimental autoimmune myositis (EAM) model was produced in SJL/J mice by an immunization with rabbit myosin B (MB) fraction. In this model, the plasma level of anti-MB antibody was elevated, and mouse IgG and complement C3 were deposited in the muscle fibres. Administration of IVIG dose-dependently reduced the incidences of necrotic and inflammatory changes in the skeletal muscle. IVIG treatment also decreased the elevation of anti-MB antibody level, as well as the deposition of IgG and C3. We next evaluated the effect of IVIG in adoptive EAM mice made by an intravenous injection of lymph node cells previously stimulated with MB. Adoptive EAM mice showed similar lesions in skeletal muscle as EAM mice and IVIG inhibited the lesion development. In vitro experiments demonstrated that IVIG inhibited complement-mediated lysis of human erythrocytes sensitized with anti-human erythrocyte antibodies. The binding of C1q, C4 and C3 to the same cells was also inhibited by IVIG. Taken together these findings suggest that IVIG prevents the development of myositis in EAM and adoptive EAM models by several mechanisms, such as reducing anti-myosin antibody and by blocking complement activation. Our present findings might account for the clinical efficacy of IVIG in PM and DM patients.     

Efficacy of IVIG affinity-purified anti-double-stranded DNA anti-idiotypic antibodies in the treatment of an experimental murine model of systemic lupus erythematosus

Since the idiotypic network is an important mechanism for controlling the immune repertoire, we tested anti-idiotypic modulation employing concentrated specific natural polyclonal anti-double-stranded (ds) DNA anti-idiotypic antibodies obtained from a commercial IVIG in the treatment of experimental systemic lupus erythematosus (SLE). Specific natural polyclonal anti-dsDNA anti-idiotypic antibodies (IVIG-ID) were affinity purified from IVIG on an anti-dsDNA-Sepharose column constructed from anti-dsDNA idiotypes (ID) affinity purified from 55 patients with active SLE. NZB/W F(1) mice were treated i.v. with 3 weekly injections of IVIG-ID (2 mg/kg/injection) or regular IVIG (400 mg/kg/injection) both before (age 8 weeks) and after developing anti-dsDNA antibodies at the age of 21-22 weeks. The IVIG-ID-treated mice showed a decline in the titer of anti-dsDNA antibodies during the treatment, reaching maximum suppression 1 week after the last injection. A significant difference in the proteinuria level in the IVIG-ID-treated group compared to the control group was observed. Immunohistology showed different patterns of IgG deposition, with mesangial and capillary wall deposits in controls and in the IVIG-treated group, but only mesangial deposits in the IVIG-ID-treated group. The survival time of the IVIG-ID-treated group was longer than the IVIG-treated group. Treatment with concentrated specific anti-dsDNA anti-ID prepared from commercial IVIG is more effective in suppressing the humoral reaction and clinical signs of SLE than native IVIG. These results point to the considerable regulatory role of anti-ID in the mechanism of action of IVIG in SLE.     

Comparative cytological study of lymph node tuberculosis in HIV-infected individuals and in patients with diabetes in a developing country

Tuberculosis (TB) is a common infection affecting patients with human immunodeficiency virus (HIV) and diabetes mellitus (DM). With the increasing incidence of HIV infection and DM in a developing country like India, TB is definitely on the rise. In a given population, one expects to see these three diseases in varying combinations, such as HIV and TB, DM and TB, HIV and DM with TB. In such combinations TB may lack the characteristic clinical and histological picture due to the associated depressed cell-mediated immunity seen in both diseases and TB may have an unusual clinical presentation and cytology picture. In this retrospective study of 36 months, from January 1997 to December 1999, 109 cases diagnosed cytologically as tuberculous lymphadenitis and tested for HIV infection and investigated as well for DM were selected. Forty-six (42%) were nondiabetic HIV patients, 13 (12%) were non-HIV DM patients, and 50 (46%) had TB without HIV infection or DM. The coexistence of both HIV and DM was not noted. The cytomorphological characteristics supplemented by culture studies of each of these three groups were compared in detail and based on these four cytological patterns, Pattern 1, Pattern 2, Pattern 3, and Pattern 4 emerged and were characterized. This study highlights the usefulness of cytomorphology of the lymph nodes to characterize the cytopathological profile of TB in both HIV and DM, which have many clinical and immunological similarities, and indirectly postulate the extent of immune suppression and evolve effective strategies in the management of coexisting diseases. Such a comparative study has not been carried out in the past.     

Influence of diabetes mellitus on immunity to human tuberculosis

Type 2 diabetes mellitus(DM) is a major risk factor for the development of active pulmonary tuberculosis (TB), with development of DM pandemic in countries where TB is also endemic. Understanding the impact of DM on TB and the determinants of co‐morbidity is essential in responding to this growing public health problem with improved therapeutic approaches. Despite the clinical and public health significance posed by the dual burden of TB and DM, little is known about the immunological and biochemical mechanisms of susceptibility. One possible mechanism is that an impaired immune response in patients with DM facilitates either primary infection with Mycobacterium tuberculosis or reactivation of latent TB. Diabetes is associated with immune dysfunction and alterations in the components of the immune system, including altered levels of specific cytokines and chemokines. Some effects of DM on adaptive immunity that are potentially relevant to TB defence have been identified in humans. In this review, we summarize current findings regarding the alterations in the innate and adaptive immune responses and immunological mechanisms of susceptibility of patients with DM to M. tuberculosis infection and disease.     

大剂量免疫球蛋白静脉注射治疗系统性红斑狼疮的临床观察

目的观察大剂量免疫球蛋白静脉注射（IVIG）治疗系统性红斑狼疮（SLE）的疗效及不良反应。方法应用大剂量免疫球蛋白[0.4g/（kg·d）,3～5d]静脉注射治疗16例重症SLE,观察治疗前后患者临床症状及实验室检查的变化,同时了解有无不良反应的发生。结果大剂量免疫球蛋白静脉注射后,SLE患者的临床症状（如发热、皮损、关节痛等）明显改善,同时患者的狼疮活动积分、ds-DNA抗体、血沉明显降低（P均〈0.01）,补体、血小板明显增高（P〈0.05）,但24h尿蛋白改善不明显。3例患者使用IVIG后出现不良反应。结论大剂量免疫球蛋白静脉注射治疗重症系统性红斑狼疮有较好的疗效,但应注意避免其不良反应的发生。     

Type 2 diabetes mellitus is associated with altered CD8+ T and natural killer cell function in pulmonary tuberculosis

Type 2 diabetes mellitus (DM) is associated with expanded frequencies of mycobacterial antigen-specific CD4⁺ T helper type 1 (Th1) and Th17 cells in individuals with active pulmonary tuberculosis (TB). No data are available on the role of CD8⁺ T and natural killer (NK) cells in TB with coincident DM. To identify the role of CD8⁺ T and NK cells in pulmonary TB with diabetes, we examined mycobacteria-specific immune responses in the whole blood of individuals with TB and DM (TB-DM) and compared them with those without DM (TB-NDM). We found that TB-DM is characterized by elevated frequencies of mycobacterial antigen-stimulated CD8⁺ T cells expressing type 1 [interferon-γ and interleukin-2 (IL-2)] and type 17 (IL-17F) cytokines. We also found that TB-DM is characterized by expanded frequencies of TB antigen-stimulated NK cells expressing type 1 (tumour necrosis factor-α) and type 17 (IL-17A and IL-17F) cytokines. In contrast, CD8⁺ T cells were associated with significantly diminished expression of the cytotoxic markers perforin, granzyme B and CD107a both at baseline and following antigen or anti-CD3 stimulation, while NK cells were associated with significantly decreased antigen-stimulated expression of CD107a only. This was not associated with alterations in CD8⁺ T-cell or NK cell numbers or subset distribution. Therefore, our data suggest that pulmonary TB complicated with type 2 DM is associated with an altered repertoire of cytokine-producing and cytotoxic molecule-expressing CD8⁺ T and NK cells, possibly contributing to increased pathology.     

MBL2 polymorphisms – manifestations in Bulgarian patients with adult dermatomyositis and systemic lupus erythematosus

Deficiency in some complement factors is known to cause both systemic lupus erythematosus (SLE) and dermatomyositis (DM). Mannose‐binding lectin (MBL) is a recognition molecule of the lectin pathway, and its low levels are reported to influence some autoimmune diseases. Furthermore, MBL2 polymorphisms have been described associated with low MBL serum levels due to impaired MBL structure and function. This is a pilot study to investigate the role of MBL2‐550G/C (H/L), ‐221G/C (Y/X), Arg52Cys (D), Gly54Asp (B), Gly57Glu (C) polymorphisms and MBL serum levels as a risk factor for a development of adult DM and SLE in Bulgarian patients. None of the studied MBL2 polymorphisms appeared associated with the diseases investigated. However, we have found an increased OR of MBL2‐221XY genotype in the patients with SLE (OR 1.64, 95%CI 0.77–3.52). MBL2 polymorphisms seemed to affect MBL serum levels and to be associated with the clinical features although none of the associations remained statistically significant after Bonferroni correction. The‐550L allele showed an association with electromyography findings in patients with DM. The‐221XY genotype was associated with photosensitivity in patients with SLE. The 54AB genotype showed an association with malar rash in patients with SLE, but it appeared decreased among SLE patients with ANA. In conclusion, our results suggest that the MBL2 polymorphisms have rather a disease modifying role and they are not associated with the disease susceptibility in adult DM and SLE among Bulgarian patients.     

Pathogenic anti-DNA idiotype-reactive IgG in intravenous immunoglobulin preparations.

This study was addressed to explore the reactivity of natural anti-idiotypes from commercial lots of immunoglobulins to several idiotypes (Ids), usually expressed by anti-DNA molecules in lupus nephritis. Eleven intravenous immunoglobulin (IVIG) preparations and nine (three polyvalent and six hyper-immune) intramuscular IgG were investigated for specific content of anti-DNA, anti-F(ab')2 and antibodies reacting with several anti-DNA IgG Ids. Two samples (nos 6 and 11) showed high reactivity with allogeneic F(ab')2 and with F(ab')2 of myeloma proteins bearing the anti-DNA Id 3I+ and the 8.12+. Since both 3I and 8.12 Id markers are known to characterize pathogenic anti-DNA IgG in systemic lupus erythematosus (SLE), anti-Id antibodies to these markers were obtained by absorbing the IVIG samples nos 6 and 11 to Sepharose columns coupled with pooled F(ab')2 fragments of 3I(+)-F4(+)-8.12(+)-myeloma proteins. Inhibition experiments showed that anti-8.12 Id-eluted IgG induced a selective suppression of the DNA-reactive antibodies derived from patients with active lupus nephritis to their substrate, suggesting the involvement of 8.12+ molecules in the SLE glomerular damage. Since 8.12+ anti-DNA are nephritogenic antibodies, the occurrence of anti-8.12+ Id in commercial IVIG may be of potential therapeutic relevance in modulating the pathogenic SLE Id network. Previous variable results of IVIG treatment in SLE, such as resolution of proteinuria or worsening nephritis, could be related to variable enrichment of different lots of IVIG in suppressive anti-pathogenic Id antibodies.     

Antiviral function and efficacy of polyvalent immunoglobulin products against CMV isolates in different human cell lines

Primary infection and reactivation of human cytomegalovirus (CMV) remain a major problem in immunocompromised patients, frequently resulting in a life threatening CMV disease. Intravenous polyvalent (hyper)-immunoglobulins (IVIG) can be administered for therapy and prophylaxis of CMV infections. However, only limited data about the efficacy and mechanism of action of IVIG products against viral infections in vitro are available so far. In this study, the effect of IVIG on CMV infection in vitro was investigated using isolates from CMV-infected patients as well as the laboratory strains AD169 and TB40. A qualitative and quantitative comparison of five different commercially available IVIG products in different human cell lines was performed concerning their ability (1) to neutralize cell-free virus, (2) to inhibit cell-to-cell spread and cell-associated transmission and (3) to influence CMV mRNA levels. All IVIG tested exhibited a high neutralization activity in epithelial and endothelial cell cultures (50% inhibition dose <0.1 mg/ml). However, qualitative differences between the products could be demonstrated in neutralization tests using human embryonal lung fibroblasts (HELF). The IVIG products also significantly differed in their ability to inhibit cell-to-cell spread within an CMV-infected HELF monolayer displaying inhibition rates that varied between 61 and 100%. No correlation between the ability to neutralize cell-free virus and to inhibit cell-to-cell spread could be observed. The incubation with IVIG influenced the amount of CMV immediate early and late mRNA, as indicated by a significant reduction in CMV mRNA in infected epithelial cells after incubation with IVIG in a dose-dependent manner. This study suggests different antiviral functions of polyvalent IVIG and confirms their potential to inhibit a CMV infection in vitro, with profound differences between the hereby used IVIG products.     

Effect of IVIG on the hair regrowth in a common variable immune deficiency patient with alopecia universalis.

Common variable immune deficiency (CVID) is associated with a variety of autoimmune diseases. Alopecia universalis (AU), believed to have an autoimmune basis, has been found in 1.6% of patients with CVID. Intravenous immunoglobulin (IVIG) therapy is used in various immunodeficiency disorders including CVID, and benefit has been shown in the therapy of autoimmune diseases. We report a patient with CVID and AU treated with IVIG who experienced significant hair regrowth. An 8-year-old girl with CVID and AU was treated with IVIG 400 mg/kg every 4 weeks. Since her second dose of IVIG, regrowth of eyelashes, eyebrows, body and scalp hair was observed in this patient. At present, about 1 year treat-meant of IVIG, significant hair regrowth is noted with 5-6 cm of scalp hair. We believe that IVIG may be beneficial in the treatment of AU, at least in patients with CVID.     

Elevated circulating levels of monocyte activation markers among tuberculosis patients with diabetes co-morbidity

Alteration in the frequency of monocyte subsets is a hallmark of tuberculosis–diabetes co-morbidity (TB-DM). To study this association, we examined the plasma levels of sCD14, sCD163, C-reactive protein (CRP) and soluble tissue factor (sTF) in individuals with TB-DM, TB or diabetes mellitus (DM), and in healthy controls (HC). Circulating levels of sCD14, sCD163 and sTF were significantly increased in TB-DM and DM compared with TB and HC; however, CRP was significantly increased in TB-DM and TB compared with DM and HC. During longitudinal follow up, sCD14, CRP and sTF levels remained significantly increased in TB-DM compared with TB from baseline (pre-treatment), during treatment (2nd month) and at the completion (6th month) of anti-TB treatment (ATT), whereas sCD163 was significantly higher in TB-DM compared with TB only at baseline. Moreover, the levels of sCD14 and sCD163 were significantly higher in TB-DM individuals with bilateral and cavitary disease and exhibited a significant positive relationship with bacterial burden. Levels of sCD14, sCD163 and CRP exhibited a positive relationship with HbA1c levels. Within the TB-DM group, those with known diabetes before incident TB (KDM) exhibited significantly higher levels of sCD14 and sCD163 compared with individuals with newly diagnosed DM with TB (NDM). Finally, KDM individuals on metformin treatment exhibited significantly lower levels of sCD14, sCD163 and CRP compared with those on non-metformin-containing regimens. Our data demonstrate that systemic monocyte activation marker levels reflect baseline disease severity and extent in TB-DM, differentiate KDM from NDM and are modulated by ATT and metformin therapy.     

Intravenous Immunoglobulins as a new opportunity to treat discoid lupus erythematosus: A case report and review of the literature

Discoid lupus erythematosus (DLE) is a chronic dermatological disease that can lead to scarring, alopecia and dyspigmentation, if not properly treated. Actually, no drugs are specifically approved for the treatment of CLE, although the first-line therapy usually consists of photoprotection associated to topical or oral steroids, topical calcineurin inhibitors and hydroxychloroquine (HCQ). In cases of DLE refractory to these medications, many other agents have been employed, such as dapsone, methotrexate, azathioprine, cyclophosphamide, biologic drugs and Intravenous Immunoglobulin (IVIG).We described the case of a DLE patient resistant to combination therapy with steroid and HCQ who was successfully treated with cyclical IVIG therapy. The treatment with IVIG resulted rapidly effective with persistent efficacy and low rates of relapses, although more cycles of IVIG are needed to achieve a stable clinical remission.We also discussed the beneficial and promising effects of IVIG in patients with Cutaneous Lupus reporting the previously published data.     

Don’t neglect the rare adverse event with intravenous immunoglobulin: Hemolytic anemia

Intravenous immunoglobulin (IVIG) associated hemolytic anemia is an under-recognized complication of IVIG therapy. The incidence of this adverse event is not clear. Patients at high risk for IVIG-associated hemolytic anemia include non-O blood group recipients and those undergoing high-dose administration for inflammatory or autoimmune disorders. Here, two different cases of IVIG-associated hemolytic anemia are demonstrated. The first patient, a 66 year-old male with Guillain-Barré syndrome, had a severe attack for which erythrocyte replacement was required. Mild hemolysis was detected during IVIG administration in the second patient, a 57 year-old female with chronic immune thrombocytopenic purpura. Following IVIG termination, the hemolysis diminished gradually. Although it is rare and often manageable, clinicians should be aware of and monitor patients for hemolytic anemia following IVIG therapy.     

Intravenous immunoglobulin replacement therapy in X-linked agammaglobulinemia]

Intravenous immunoglobulin (IVIG) replacement therapy is the mainstay of therapy for X linked agammaglobulinemia (XLA). This study was attempted to investigate how patients with XLA were treated with IVIG in Japan. Data were complied from questionnaires filled in by the physicians. One hundred eighteen medical records had been given from 134 patients. One hundred eleven patients had been treated with IVIG. Most patients had been administered IVIG every 2 to 4 weeks, and maintained serum IgG trough levels of 400 mg/dl. Some of patients had adverse effects of IVIG. Antibiotics, especially macrolides, had been administered in some of patients. A few patients, despite the maintenance of higher trough levels, were associated with infections. The present study suggests that IVIG should be administered dependent on personal infection histories.     

Effect of intravenous gammaglobulin therapy in IgG2 deficient and IgG2 sufficient children with recurrent infections and poor response to immunization with Hemophilus influenzae type b capsular polysaccharide antigen

Nine children with recurrent sinopulmonary infections and normal IgG levels failed to improve after a 12-month period of prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole. Five of these children had selective deficiency of IgG2 subclass, while the other four did not, but all nine children had a poor response to immunization with Hemophilus influenzae type b (Hib) capsular polysaccharide. Following the institution of intravenous immunoglobulin (IVIG) therapy, there was a significant decrease in the episodes of sinusitis and otitis media in all patients. Intravenous immunoglobulin therapy resulted in a significant increase in total serum IgG, IgG2, and IgG anti-Hib antibody levels. Discontinuation of IVIG therapy was followed by the return of recurrent infections. This preliminary study demonstrates that IVIG replacement therapy in children with recurrent infections and selective antibody deficiency is associated with a significant reduction in the frequency of sinopulmonary infections.