Intravenous immunoglobulin (IVIg) is usually a human polyspecific IgG (presented as monomeric or multimeric forms) and derives from the plasma of thousands healthy individuals (3,000-80,000)

Intravenous immunoglobulin (IVIg) is usually a human polyspecific IgG (presented as monomeric or multimeric forms) and derives from the plasma of thousands healthy individuals (3,000-80,000).53 IVIg has been increasingly used during the last decades for an growing number of systemic immune-mediated and heterogeneous inflammatory diseases The mechanism of high-dose IVIg remains unclear, but probably works in multiple fronts, such as blocking the binding of serum immunoglobulins, B cell surface immunoglobulins, and T cell antigen receptors to their respective antigens.54 IVIg reduced skin fibrosis and inhibited IL-4 and TGF- production in tight skin (TSK) mice.55 In two small open-label studies in patients with SSc, IVIg reduced histological skin fibrosis and joint pain and improved hand function.56,57 A recent double-blind multi-center RCT in 63 patients with diffuse cutaneous SSc (dcSSc) concluded that IVIg improved skin score especially after multiple courses.58 Serious adverse reactions are rare and include arterial thrombosis, severe anaphylaxis, aseptic meningitis, and renal tubular crisis. internal organs, and looks very promising, as modification of transplantation immunosuppression is usually decreasing the early high mortality. KEYWORDS: abatacept, autologous stem cells, belimumab, cyclophosphamide, Intravenous immunoglobulin, immunomodulation, methotrexate, mycophenolate mofetil, tocilizumab, transplantation Introduction Systemic sclerosis Secretin (rat) (SSc) is usually a chronic connective tissue disease (CTD), which affects skin, blood vessels, lungs, heart, kidneys, gastrointestinal (GI) tract and musculoskeletal system. It is characterized by three cardinal features: early microvascular obliterative changes, activation of the immune system and widespread fibrosis of skin and internal organs. Involvement of internal organs results in significant morbidity and mortality. Microvascular changes are exemplified by Raynaud’s phenomenon (RP) and microvascular injury seen as nailfold capillaroscopy abnormalities, whereas immune activation is usually exemplified by SSc-related autoantibodies (auto-Abs).1C3 Systemic sclerosis affects all races and may be diagnosed at any age although most cases develop in individuals aged 20C60?years. As data continue to gather from around the world, it is shown that while the incidence of SSc exhibit remarkable variation across different geographic regions (ranging 2C23 cases per million), it appears to rise over the past three decades. Prevalence is also documented to span between 46C655 cases per million among different centers.4,5 Female predominance is evident among cases with limited SSc, while ACH diffuse SSc appear to affect males and females at more comparable rates.2C6 SSc is considered to be a chronic, gradually deteriorating disease across several months to years. Some cases can stabilize for prolonged periods of time while others, primarily with diffuse disease, show a fulminate clinical course with detrimental consequences within few months. Mortality as well morbidity among patients with scleroderma is usually increased. Ten-year cumulative survival rate was found 66% during the 1990s.7 Major morbidity is related to the type and extent of internal organ involvement, such as pulmonary fibrosis and/or pulmonary hypertension that often lead to severe dyspnoea and oxygen dependence.6 GI tract Secretin (rat) involvement includes both the upper (common) and the lower part (less common); it may also be quite severe leading to malnutrition and death. 8 Infections also play significant role for the increased morbidity and mortality of patients with SSc. Propensity to infections is derived from both poor functional status and immunosuppressive treatment. Hand dysfunction due to tight skin, joint contractures and ulceration of the fingertips represent a common disabling factor among patients with SSc, which also leads to significant morbidity due to pain, frequent injuries, gangrene secondary to ischemia and self-amputations.6 In overall diffuse skin disease, male gender, Secretin (rat) older age at onset, cardiopulmonary involvement, renal crisis and the absence of Raynaud’s phenomenon as the initiating clinical symptom represent bad prognostic factors.9,10 Vascular abnormalities and immune abnormalities appear early in the disease Secretin (rat) course and are likely to drive the pathogenetic cascade of the disease. SSc-related auto-Abs, such as anti-topoisomerase I (anti-Topo; formerly anti-Scl70), anti-centromere (ACA), and anti-RNA polymerase III auto-Abs, appear before, and sometimes years before clinical fibrosis.2 Longitudinal skin biopsies from patients with SSc reveal inflammatory infiltrates early before histological fibrosis, but as the disease progresses inflammatory infiltrates greatly diminish and fibrosis dominates the histological picture.11 Pro-fibrotic cytokines, such as transforming growth factor (TGF), are considered pivotal for the disease pathogenesis. Evidence from animal models and in vitro studies indicates that T cells through cell contact, and cytokines activate fibroblast to produce collagen.3,12 Increased levels of T cell cytokines, including the pro-fibrotic IL-4 and IL-13 (Th2 cells), are seen in peripheral blood from SSc patients.13,14 Although aberrations in the expression of individual cytokines may be shared among several different diseases, it is obviously the fine combination of several abnormalities that lead to systemic collagen disposition, a feature unique to SSc among other systemic autoimmune diseases underscoring the complexity of the cellular controls operating in enhancing or suppressing the profibrotic response.15,16 Mononuclear cell infiltrates, consisting mainly of T cells and macrophages, appear very early in the disease process.17 B cells are hyperactivated in SSc, as indicated by the overexpression of the stimulatory CD19 receptor and impairment of the inhibitory CD22 receptor.18 B cells contribute to disease.