Treatment of intractable pulmonary hemorrhage in two patients with childhood systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology with multisystem involvement. A number of pulmonary complications including pleuritis, pneumonitis, infectious pneumonia, and pulmonary hemorrhage, have been reported in patients with SLE. Pulmonary hemorrhage is a major life-threatening manifestation in children and adolescents with SLE. Mycophenolate mofetil is an immunosuppressive agent used in solid organ transplantation, and it may play an increasing role in autoimmune disease. In this report, we present two cases of childhood SLE with recurrent pulmonary hemorrhage, which were unresponsive to treatment with high-dose corticosteroids, cytotoxic therapy, IVIG, plasmaphoresis, and supportive therapy, but responded to IV mycophenolate mofetil. A multimodal therapy including mycophenolate mofetil was effective in treatment of these two children.     

Novel therapies in lupus nephritis

Renal disease continues to cause major morbidity and some mortality for around 30-40% of patients with systemic lupus erythematosus (SLE). Although the combinations of prednisolone and azathioprine or prednisolone and cyclophosphamide have been beneficial to many patients with SLE, they are not always effective and have significant side effects. It is very encouraging that new immunosuppressive drugs such as mycophenolate mofetil and more targeted therapies e.g., anti-CD20 are coming rapidly to larger scale clinical trials. The treatment of lupus nephritis is set to change quite rapidly in the next decade. In this review we highlight the likely major therapeutic advances.     

Cytomegalovirus disease of the upper gastrointestinal tract in patients with rheumatic diseases: a case series and literature review

Cytomegalovirus disease of the upper gastrointestinal tract (CMV-UGT) is a rare but significant complication in patients with rheumatic diseases. We reviewed records for January 2004 to December 2012 and investigated the occurrence of CMV-UGT in patients with rheumatic diseases to evaluate clinical characteristics, the value of the CMV antigenemia assay, and the association between immunosuppressive therapy and CMV-UGT. Ten CMV-UGT events (six gastric ulcer, two esophagitis, one gastritis, and one duodenal ulcer) in nine patients (three rheumatoid arthritis, three systemic lupus erythematosus, one dermatomyositis, one systemic sclerosis, and one overlap syndrome) were identified based on pathology. Mean age was 66.5 (range, 53–76)?years. The CMV antigenemia assay was negative in five cases (50 %). All ten cases received glucocorticoids and six (60 %) received pulsed glucocorticoids. Mean prednisolone dose was 31.3 (range, 7.5–40)?mg/day at diagnosis. Concomitant immunosuppressive agents were used in eight cases (80 %). Considering other published cases, the most common immunosuppressive drug was cyclophosphamide (ten cases; 45 %). Notably, two of our patients who were treated with low-dose glucocorticoids plus other milder immunosuppressive drugs (methotrexate and cyclosporine) also developed CMV-UGT. Life-threatening complications such as massive bleeding or perforated ulcer occurred in two patients. These results suggest that patients receiving intensive immunosuppressive therapy such as high-dose glucocorticoids and cyclophosphamide are at higher risk for developing CMV-UGT. Moreover, CMV-UGT can occur even with low-dose glucocorticoid therapy and relatively mild immunosuppressive agents. The value of the CMV antigenemia assay for predicting CMV-UGT appears to be limited.     

Treatment of lupus nephritis

Lupus nephritis is a relevant source of morbidity and mortality in patients with systemic lupus erythematosus. The standard therapy of remission induction in severe lupus nephritis is based on the use of monthly intravenous cyclophosphamide. Recent data have established that the maintenance of remission in lupus nephritis can be achieved with azathioprine or mycophenolate mofetil, with less adverse effects than quarterly intravenous cyclophosphamide. In recent years, a number of controlled randomized clinical trials have been published, opening new therapeutic options in the induction of remission in lupus nephritis, such as less aggressive regimens of intravenous cyclophosphamide or mycophenolate mofetil. Further studies are needed for establishing the optimal therapy of lupus nephritis patients.     

Opportunistic infections mimicking gastrointestinal vasculitis in systemic lupus erythematosus.

Patients with systemic lupus erythematosus who are on chronic immunosuppressive therapy are at risk for developing infectious complications. We present 2 cases of immunosuppressed patients with systemic lupus erythematosus who presented with abdominal complaints without other systemic lupus symptoms. These patients were initially thought to have gastrointestinal vasculitis based on preliminary pathologic reports; however, further workup and careful review of the pathologic specimens confirmed an opportunistic infection as the etiology in each case. It is critical that physicians maintain a high index of suspicion for infection when treating immunocompromised patients with systemic lupus erythematosus with abdominal complaints to avoid delay in appropriate treatment.     

Mycophenolate mofetil for the treatment of systemic lupus erythematosus: an open pilot trial

OBJECTIVE: To investigate the effectiveness and safety of mycophenolate mofetil in patients with systemic lupus erythematosus who were inadequately controlled with corticosteroids, antimalarials, and other immunosuppressive agents. METHODS: Ten patients with systemic lupus erythematosus (SLE) were treated with 1500-2000 mg mycophenolae mofetil (MMF) daily for a median observation time of 11. 2+/-2.4 (8-16) months in an open clinical trial. The effectiveness and safety of treatment were analyzed using an established disease activity score, clinical status, and laboratory parameters. RESULTS: All patients improved under treatment with no or only minor side effects. The disease activity score (SLAM) decreased statistically significantly from a median of 15.6+/-5.5 to 9.9+/-4.1 after three months (P<0.01) and to 8.0+/-3.3 after six months (P<0.01). Hematologic parameters did not change significantly whereas a reduction of inflammatory markers was observed. Four patients with SLE-nephritis already treated with cyclophosphamide pulse therapy continuously showed a slight improvement of renal function. Prednisolone dosages could be reduced significantly from a median level of 10.0+/-5.1 mg/d before treatment to 4.6+/-3.5 mg/d after six months (P<0.01). CONCLUSION: Mycophenolate mofetil is a promising option in immunosuppressive treatment of patients with moderate and severe systemic lupus erythematosus who did not show a satisfactory response to other immunosuppressives.     

Short story of antirheumatic therapy.VIII. The immunodepressants

The use of immunosuppressive drugs in rheumatology is fairly recent, starting just after the Second World War with the introduction of the first alkylating agents in oncohematology. When it became clear that some rheumatic diseases, particularly rheumatoid arthritis and systemic lupus erythematosus, showed an immune-mediated pathogenesis, including proliferation of immunocompetent cells, an application was soon found for immunosuppressive drugs in their treatment. This review outlines the historical milestones that led to the current use of drugs belonging to the major groups of immunosuppressants, i.e. alkylating agents (cyclophosphamide), folic acid (methotrexate) and purine (azathioprine) antagonists. We will also talk about the history of cyclosporin A, the first "selective" immunosuppressive agent, and that of some immunoactive drugs used more recently in rheumatology, such as mycophenolate mofetil, dapson and thalidomide.     

Advances in immunosuppressive drug therapy for use in autoimmune disease and systemic vasculitis

Several recent advances in the use of immunosuppressive drugs in autoimmune disease are relevant to management of autoimmune pulmonary disease. Sequential immunosuppression combining remission induction with cyclophosphamide with less toxic maintenance therapy such as azathioprine, methotrexate, or mycophenolate mofetil is described in Wegener's granulomatosis, systemic vasculitis, and lupus. Less aggressive forms of diseases that have been routinely treated with cyclophosphamide have been treated with alternate regimens (e.g., methotrexate treatment of limited Wegener's granulomatosis, and mycophenolate mofetil for lupus). Finally, strategies to minimize severe side effects of immunosuppression include genetic testing for predisposition to drug toxicity and proposed techniques for fertility preservation during cyclophosphamide treatment. We review established principles of immunosuppressive drug use and focus on clinical trials in autoimmune diseases that illustrate therapeutic approaches which are likely to be applied more widely in the future. More detailed reviews of treatment of individual diseases will be found in elsewhere in this issue.     

Late recurrence of lupus nephritis in a renal transplant recipient: response to mycophenolate mofetil

Clinically significant recurrence of lupus nephritis in the renal allograft is low, with an incidence of 1 to 3%, and usually occurs within the first 6 years after transplantation. We report an unusual case of a patient with end-stage renal disease caused by lupus nephritis who received a kidney transplant from a living relative; 13 years later, the patient had a severe recurrence of diffuse proliferative lupus nephritis. The patient relapsed after receiving intravenous cyclophosphamide therapy and had a partial response to oral mycophenolate mofetil. In this report we review the risk factors for the recurrence of the systemic lupus erythematosus in the kidney graft and the anti-lupus activity of mycophenolate mofetil.     

Refractory immune thrombocytopenia in systemic lupus erythematosus: response to mycophenolate mofetil

Immune thrombocytopenia (IT) is a common manifestation of systemic lupus erythematosus (SLE). Although severe IT (<20 x 10(9)/L) occurs in about 5-10% of patients, usually in the context of active disease, the absence of randomized controlled trials has not allowed the development of evidence-based guidelines for managing this condition. Conventionally, high-dose glucocorticoids are considered first-line therapy. Adjunctive medical and surgical treatments for patients with an absent or partial response to glucocorticoids have met with varying degrees of success. We describe an SLE patient with IT refractory to high-dose corticosteroids, pulse methylprednisolone and intravenous immunoglobulin therapy, whose platelet counts normalized during therapy with mycophenolate mofetil (MMF). Pending further controlled studies to confirm this observation, we suggest that MMF may be considered as a therapeutic option in the treatment of glucocorticoid-refractory immune thrombocytopenia in SLE.     

?Cuál es el mejor tratamiento de mantenimiento de la nefritis lúpica tipo IV?

Up to two-thirds of patients with systemic lupus erythematosus develop renal disease at some stage of their disease. Diffuse proliferative forms (type IV) have the worst prognosis due to the risk of progression to chronic renal insufficiency (CRI). In these patients, aggressive immunosuppressive therapy is required to induce clinical remission, followed by maintenance therapy to preserve renal function.The first clinical trials demonstrated the need for maintenance therapy in these severe forms; regimens consisting of intravenous cyclophosphamide (CYF) administered quarterly after the induction phase reduced the risk of progression to CRI. Subsequently, because of the long-term risk posed by extended courses of CYF, the use of mycophenolate mofetil (MMF) and azathioprine for maintenance therapy was investigated. In patients with proliferative lupus nephritis, AZA and MMF are good options for maintenance therapy, but are not superior to CYF pulses. Current information on maintenance therapy in proliferative lupus nephritis is based on a small number of studies with major methodological limitations.Consequently, there is clearly a need for further well-designed studies of the most recent therapeutic options. Equally, control of cardiovascular risk factors and the use of additional therapies that avoid the adverse effects of these immunosuppressive agents are required to improve the management of patients with type IV lupus nephritis.     

Short-term add-on tocilizumab and intravenous cyclophosphamide exhibited a remission-inducing effect in a patient with systemic lupus erythematosus with refractory multiorgan involvements including massive pericarditis and glomerulonephritis

We report on a 41-year-old woman with refractory systemic lupus erythematosus with massive pericarditis, macrophage activation syndrome, and glomerulonephritis despite high-dose glucocorticoids and tacrolimus. Tocilizumab dramatically improved pericarditis, and glomerulonephritis was controlled after adding cyclophosphamide. We had to halt tocilizumab and cyclophosphamide due to possible pneumocystis infection after five and three infusions of tocilizumab and intravenous cyclophosphamide, respectively. Nevertheless, no lupus flare had been observed on glucocorticoid monotherapy and enabled further rapid tapering prednisolone.     

Cyclophosphamide: new approaches for systemic lupus erythematosus

Cyclophosphamide remains the 'gold standard' treatment for severe organ threatening systemic lupus erythematosus (SLE), especially renal and central nervous system lupus. Intravenous and oral cyclophosphamide have been compared, retrospectively, with similar two year remission rates of 73% and 90%. In a meta-analysis, intravenous cyclophosphamide with oral prednisone is more effective than oral prednisone alone. The efficacy of cyclophosphamide in lupus nephritis has been proven in multiple clinical trials, but efficacy has to be balanced with toxicity, including infection, gonadal failure, and malignancy. Although the continued use ofcyclophosphamide for renal lupus has been challenged by a recent trial of mycophenolate mofetil, and may be challenged in the future by planned trials of biologics, it continues to be widely used. This review will touch on the traditional intravenous 'pulse' cyclophosphamide regimen, consider its toxicity, and contrast it with newer approaches to cyclophosphamide.     

Optimum therapeutic approaches for lupus nephritis: what therapy and for whom?

The optimum therapy for patients with lupus nephritis is a hotly debated topic. Prospective randomized studies in patients with proliferative lupus nephritis have established the superiority of cyclophosphamide to azathioprine, both of which are used in combination with corticosteroids. Although high-dose, intermittent administration of cyclophosphamide (pulse therapy) has significantly reduced the toxicity associated with this drug, premature ovarian failure and infections remain considerable problems. Short-term to intermediate-term, randomized controlled trials have shown that mycophenolate mofetil is a good option for the induction and maintenance of remission in lupus nephritis patients. Additional longer-term trials involving more patients and stricter outcomes based on renal function are needed, however, before claims that mycophenolate mofetil is superior to cyclophosphamide can be substantiated. Until such data are available, physicians caring for patients with lupus nephritis can use mycophenolate mofetil as induction or maintenance therapy for selected patients under close observation. Small noncontrolled trials with short-term follow-up suggest that up to 50% of patients who are refractory to cyclophosphamide might have a clinically significant response to rituximab, a monoclonal antibody directed against B cells.     

Systemic lupus erythematosus--2005 annus mirabilis?

We are about to enter a new era in the treatment of patients with systemic lupus erythematosus (SLE). For the past 40 years hydroxychloroquine sulfate and corticosteroids, together with varying combinations of immunosuppressive drugs, have been the main treatments for SLE. Although effective for many patients, some patients fail to respond to these drugs and even more suffer from major side effects due to the generalized nature of the immunosuppression. In this article we review the remarkable confluence of new therapies ranging from newer immunosuppressive drugs with fewer side effects, such as mycophenolate mofetil, to the more targeted approaches offered by biological agents. These agents have been designed to block molecules such as CD20, CD22 and interleukin-10 that are thought to have an integral part in the development of SLE. This wolf might not yet be about to become extinct but its survival is increasingly under threat!     

Stellungnahme zum Einsatz von Mycophenolat-Mofetil beim systemischen Lupus erythematodes

Mycophenolate mofetil (MMF) is among the few immunosuppressive drugs with sufficient data from controlled studies on the therapy of systemic lupus erythematosus (SLE). In the light of results from recently published randomized controlled trials on the effectiveness of MMF in the treatment of lupus nephritis, it has become necessary to revise the statement of the Germany Society of Rheumatology on the use of MMF for SLE. In the induction therapy of lupus nephritis MMF has been shown to be equivalent in effectiveness to i.v. cyclophosphamide and superior to azathioprine in the maintenance phase. Cyclophosphamide is inferior to MMF and probably also to azathioprine as maintenance therapy and should therefore, not be considered for this purpose and also because of its toxicity. For other organ manifestations MMF also constitutes an alternative when approved immunosuppressants are not able to control the disease and glucocorticoids cannot be reduced to 7.5 mg prednisolone daily equivalents or less.     

Cerebral vasculitis in a patient with hereditary complete C4 deficiency and systemic lupus erythematosus

We describe the case of a female patient with hereditary complete C4 deficiency and systemic lupus erythematosus. She had suffered from lupus nephritis in early childhood. At the age of 23 years she developed severe lupus with skin disease and life-threatening cerebral vasculitis. Her cerebral disease was unresponsive to high-dose steroids, intravenous immunoglobulin, fresh frozen plasma and plasma exchange. Improvement was achieved with immunoadsorption in combination with mycophenolate mofetil. The patient made a complete recovery and is maintained in complete remission on mycophenolate and low-dose steroids.     

Combined immunosuppressive treatment (CIST) in lupus nephritis: a multicenter,randomized controlled study

Clinical Rheumatology - The standard strategy for treating lupus nephritis comprises glucocorticoids together with either intravenous cyclophosphamide or oral mycophenolate mofetil, but the low...     

Lupus: improving long-term prognosis

Over recent decades short- and medium-term survival has greatly improved in patients affected with systemic lupus erythematosus, but long-term prognosis still remains poor mainly due to complications of the disease and/or its treatment. To improve long-term prognosis in systemic lupus erythematosus, we should try to adopt, early in the disease course, strategies that can contribute to reducing long-term complications, including screening for and prophylaxis against infections, control of risk factors for atherosclerosis, and cancer surveillance. However, in patients with systemic lupus erythematosus all these preventive strategies are often not sufficient. Indeed, two important systemic lupus erythematosus-related factors play a relevant role in all these complications: severe disease manifestations, such as glomerulonephritis and central nervous system involvement, and corticosteroid and cyclophosphamide use. Therefore, to prevent long-term complications, we should try to control disease activity and severity using the lowest effective dosage of these drugs. Moreover, strategies directed at preventing clinical manifestations in asymptomatic antinuclear antibody-positive individuals or in antiphospholipid antibody-positive systemic lupus erythematosus patients, as well as at preventing severe manifestations in patients with mild systemic lupus erythematosus at the time of the diagnosis should be considered.     

Treatment of proliferative glomerulonephritis of systemic lupus erythematosus. Recent development and current recommendations

The prevalence of the renal involvement is estimated at 40% during the course of systemic lupus erythematosus. In more than half of cases, the histological evaluation leads to the diagnosis of a severe glomerulonephritis (class III or IV A or A/C of the 2003 ISN/RPS classification) which requires a powerful treatment aiming at the remission of the nephritis, at the prevention of relapses, and at the prevention of chronic renal failure and death, with low toxicity. This review focuses on the most important trials of the last three decades that progressively delineated the treatment regimens used for lupus proliferative glomerulonephritis with active lesions. The treatment should consist in an induction regimen followed by a maintenance regimen. Until now, the standard induction associates corticosteroids and intravenous cyclophosphamide, and the most efficient regimen for maintenance with the best tolerance profile is the association of low dose corticosteroids and azathioprine or mycophenolate mofetil. However, the use of cyclophosphamide is limited by its side effects and its cumulated dose should be reduced as much as possible. When cyclophosphamide is not considered for induction, azathioprine or mycophenolate mofetil associated with steroids may constitute an alternative regimen. However, azathioprine seems less effective than cyclophosphamide to prevent relapses and preserve the renal function on a long-term basis. Preliminary data evaluating induction with mycophenolate mofetil are promising, but ongoing trials are needed to determine if induction with mycophenolate mofetil could reach this goal.