Update on the Treatment of Granulomatosis with Polyangiitis (Wegener’s)

Granulomatosis with polyangiitis (Wegener’s) (GPA), formerly known as Wegener’s granulomatosis, is a systemic vasculitis characterized by involvement of the upper airways, lungs, and kidneys. GPA shares many features with microscopic polyangiitis (MPA), so much so that recent trials have included both vasculitides. This article focuses on GPA only, as complete management includes modalities that are unique to this disease. The current treatment of GPA is stratified based on severity. For those patients who have active but non-severe GPA and do not have contraindications, methotrexate and glucocorticoids can induce and maintain remission. For patients with severe disease, options include glucocorticoids combined with either cyclophosphamide or rituximab. When cyclophosphamide is used, it is given for 3 to 6 months, after which time it is stopped and switched to methotrexate or azathioprine for remission maintenance. In randomized trials, rituximab was found to be as effective as cyclophosphamide to induce remission of severe active GPA. Given the recency of experience with rituximab, there remain a number of questions regarding relapse rate, use of repeat courses, long-term toxicity, and combination with maintenance agents. Until these questions are answered, the choice of whether to use cyclophosphamide or rituximab must be decided between the patient and physician. For patients with relapsing disease who have had prior cyclophosphamide exposure, rituximab is an excellent option. In newly diagnosed patients, the extensive experience with cyclophosphamide and its side effect profile must be weighed against these factors with rituximab. There has been limited experience with rituximab in patients with alveolar hemorrhage requiring mechanical ventilation or rapidly progressive glomerulonephritis requiring dialysis, as these patients were excluded from the largest randomized trial. Until such data become available, cyclophosphamide remains the agent with which there has been the greatest experience for efficacy in these settings.     

Thirty years of cyclophosphamide: assessing the evidence

The ideal therapy for lupus nephritis should reduce mortality and end-stage renal disease in the long term, induce early response and remission, prevent flares, have minimal side-effects and not compromise fertility. It should also be active in all ethnic groups, widely available and cost effective. Despite 30 years' clinical experience, the ability of cyclophosphamide to meet these needs is not supported by robust evidence. The first National Institutes for Health (NIH) trial in 1986 led to a shift from oral to intravenous cyclophosphamide. The three NIH trials together then led to the dogma that high-dose intravenous cyclophosphamide is the only cytotoxic agent superior to steroids alone in lupus nephritis and to its general acceptance as the 'standard of care'. Since then, high-dose intravenous cyclophosphamide has been shown to have no impact on survival, to be less effective in black patients and to have many side-effects, particularly an unacceptable risk of premature menopause. The Euro-Lupus Nephritis Trial found that low-dose intravenous cyclophosphamide could be used as an alternative to a high-dose regimen and was associated with half as many severe infections. Other advantages include no hospitalisation and virtually no risk of premature gonadal failure. Other studies have looked at regimens in which cyclophosphamide is entirely replaced--for example, with mycophenolate mofetil--and have found fewer side-effects and better induction of remission. Intravenous cyclophosphamide is the only therapy with long-term data for reduction of end-stage renal disease. As data on other therapies accumulate, however, intravenous cyclophosphamide might no longer be considered the standard treatment for lupus nephritis.     

Wegener's granulomatosis. Long-term followup of patients treated with cyclophosphamide.

Ten patients with Wegener's granulomatosis were treated with cyclophosphamide and followed for periods up to 7 years. In all cases cyclophosphamide induced complete remissions. The mean duration of remission (to date) was 38 months. Six patients have been in remission for a mean of 46 months after cyclophosphamide was discontinued; 2 have been disease-free for 7 years. Of the 10 patients treated, only 1 relapsed and she responded to a second course of cyclophosphamide. These results indicate that cyclophosphamide is the drug of choice in Wegener's granulomatosis. The long-term effectiveness of this drug suggests that it may induce permanent remissions in certain patients with Wegener's granulomatosis.     

Immunoadsorption in systemic lupus erythematosus

Plasmapheresis and immunoadsorption (IA) have been introduced into the therapeutic strategy of patients with systemic lupus erythematosus (SLE) and severe organ involvement. Despite numerous reports about the clinical efficacy of extracorporeal treatments controlled studies have failed to show significant advantages compared with standard immunosuppressive treatment. We describe the historical development of plasmapheresis‐based IA‐techniques with special comments on substitution fluids and especially immunoglobuline (Ig) specific adsorption columns. In addition, an overview is given of our clinical experience with different columns and a new strategy of aggressive Ig lowering combined with standard cyclophosphamide pulse therapy in SLE patients with severe organ involvement.     

Cyclophosphamide,Cholinesterase and Anaesthesia*

Summary: A patient receiving cyclophosphamide suffered apnoea and respiratory insufficiency after two anaesthetics in which suxamethonium had been used whilst an anaesthetic without suxamethonium was uneventful; the plasma was found to have a lowered activity of plasma cholinesterase. Accordingly eight patients being treated with cyclophosphamide were tested for plasma cholinesterase activity; in seven there was a significantly depressed level, of the acquired type, as compared with control groups of healthy subjects and patients with comparable diseases not receiving cyclophosphamide. In two patients a fall in cholinesterase activity was demonstrable after cyclophosphamide was begun. Thus appropriate precautions should be taken with patients receiving cyclophosphamide and requiring general anaesthesia: withdrawal of cyclophosphamide, avoidance if possible of depolarising relaxant drugs, or the giving of fresh blood preoperatively to raise the level of plasma cholinesterase.     

Mycophenolate mofetil in lupus nephritis

There is an increasing body of literature suggesting the efficacy and tolerability of mycophenolate mofetil (MMF) for the treatment of lupus nephritis. The rationale for its use is based upon its successful profile as an immunosuppressive agent for prevention of allograft rejection, as well as studies in murine models of lupus which have reported improved renal function and animal survival compared to placebo. This report reviews the data regarding MMF therapy in murine lupus models, and describes the initial anecdotal experience with MMF in human lupus, especially in patients with glomerulonephritis who were unresponsive to corticosteroids and cyclophosphamide, or who had unacceptable toxicity on this standard of care regimen. The results of several nonblinded, controlled clinical trials are also described, in which MMF was compared to intravenous or oral cyclophosphamide in patients with lupus nephritis. MMF was found to be well tolerated, with most studies showing fewer infections than that associated with cyclophosphamide. Efficacy of MMF was at least equivalent to cyclophosphamide, and therefore appears to provide an alternative as a standard of care for induction and maintenance treatment of lupus nephritis.     

Solid malignancies among patients in the Wegener's Granulomatosis Etanercept Trial

OBJECTIVE: Etanercept is a soluble fusion protein designed to inhibit tumor necrosis factor (TNF). During the Wegener's Granulomatosis Etanercept Trial (WGET), a placebo-controlled trial of etanercept given in addition to standard therapy for remission induction and maintenance, more solid malignancies were observed in the etanercept group than in the group treated with standard therapy alone. This study was undertaken to further explore the potential association between anti-TNF therapy and the development of malignancy in these patients. METHODS: One hundred eighty patients with active WG were enrolled and followed up for a median of 27 months. At enrollment, disease characteristics, treatment history, specific medical history items, and information about previous WG treatments and risk factors for malignancy were recorded. During the trial, the occurrence of malignancies and other adverse events was recorded prospectively. RESULTS: All 6 solid malignancies observed during the WGET occurred in the etanercept group (P = 0.01 versus placebo group); based on a comparison of age- and sex-specific incidence rates, 1.92 solid malignancies would have been expected in this group. The solid malignancies included 2 cases of mucinous adenocarcinoma of the colon, 1 each of metastatic cholangiocarcinoma, renal cell carcinoma, and breast carcinoma, and 1 recurrent liposarcoma. There were no differences between the 2 treatment groups in sex distribution, disease severity, personal or family history of cancer, or tobacco and alcohol use. The etanercept group was older at baseline and less likely to be newly diagnosed with WG at the time of randomization. Patients who developed solid tumors were older than patients who did not. All etanercept-treated patients who developed solid tumors were also treated with cyclophosphamide during the trial. However, there were no differences between the groups in the amount of cyclophosphamide received during the trial or the percentage who had received cyclophosphamide before enrollment. There were also no differences in the mean duration of daily cyclophosphamide therapy or the maximum daily cyclophosphamide dosage before enrollment. CONCLUSION: Data from the WGET, the first substantial reported experience of the combined use of etanercept and cyclophosphamide in the treatment of WG, indicate that the combination of TNF inhibition and cyclophosphamide may heighten the risk of cancer beyond that observed with cyclophosphamide alone.     

Kidney disease in systemic lupus erythematosus

Summary Glomerulonephritis is a major determinant of outcome in patients with systemic lupus erythematosus. Persistently active lupus nephritis imposes serious threats of end-stage renal failure and cardiovascular morbidity. Sustained corticosteroid treatment has been characterized as having an uncertain net benefit on the control of lupus nephritis, mainly because these drugs have relatively weak efficacy and they have been shown to confer their own set of cardiovascular risk factors. Controlled trials of corticosteroids, azathioprine and cyclophosphamide have demonstrated that the best control of clinical activity of proliferative lupus nephritis is attained with cyclophosphamide. To date, intermittent pulse cyclophosphamide treatment has produced the most facorable balance of efficacy and toxicity in patients with lupus nephritis.     

Cyclophosphamide for lupus during pregnancy

Severe systemic lupus erythematosus often requires the use of cyclophosphamide in women of reproductive age. As cyclophosphamide is generally avoided during pregnancy because of its teratogenic risk, its impact on fetal survival is poorly understood. This is a case series of lupus patients exposed to cyclophosphamide during pregnancy. We reviewed pregnancies in patients with lupus seen at a large university hospital between October 1986 and September 2003. The pregnancies were evaluated prospectively for cyclophosphamide exposure, lupus activity, and fetal outcome. Comparison was made between pregnancies with severe lupus requiring cyclophosphamide and those that did not. We identified four pregnancies with cyclophosphamide exposure. Two pregnancies were inadvertently exposed to cyclophosphamide early in the first trimester; both resulted in first trimester miscarriages. Two patients were administered cyclophosphamide for severe lupus nephritis and thrombocytopenia during the second trimester. Soon after the administration of cyclophosphamide, both pregnancies ended with fetal demise. Pregnancies exposed to cyclophosphamide for severe lupus flare resulted in a higher rate of fetal losses than pregnancies with severe lupus but not requiring the drug (100% versus 31.25%). In conclusion we present four pregnancies exposed to cyclphosphamide, each ending with pregnancy loss. Based on our experience, the survival of the fetus is strongly in doubt when cyclophosphamide is required to treat lupus in the mother.     

Wegener granulomatosis: an analysis of 158 patients.

OBJECTIVE: To prospectively study the clinical features, pathophysiology, treatment and prognosis of Wegener granulomatosis. DESIGN: Of the 180 patients with Wegener granulomatosis referred to the National Institute of Allergy and Infectious Diseases during the past 24 years, 158 have been followed for 6 months to 24 years (a total of 1229 patient-years). MEASUREMENTS: Characteristics of clinical presentation, surgical pathology, course of illness, laboratory and radiographic findings, and the results of medical and surgical treatment have been recorded in a computer-based information retrieval system. SETTING: The Warren Magnuson Clinical Center of the National Institutes of Health. MAIN RESULTS: Men and women were equally represented; 97% of patients were white, and 85% were more than 19 years of age. The mean period of follow-up was 8 years. One hundred and thirty-three patients (84%) received "standard" therapy with daily low-dose cyclophosphamide and glucocorticoids. Eight (5.0%) received only low-dose cyclophosphamide. Six (4.0%) never received cyclophosphamide and were treated with other cytotoxic agents and glucocorticoids. Ten patients (6.0%) were treated with only glucocorticoids. Ninety-one percent of patients experienced marked improvement, and 75% achieved complete remission. Fifty percent of remissions were associated with one or more relapses. Of 99 patients followed for greater than 5 years, 44% had remissions of greater than 5 years duration. Thirteen percent of patients died of Wegener granulomatosis, treatment-related causes, or both. Almost all patients had serious morbidity from irreversible features of their disease (86%) or side effects of treatment (42%). CONCLUSIONS: The course of Wegener granulomatosis has been dramatically improved by daily treatment with cyclophosphamide and glucocorticoids. Nonetheless, disease- and treatment-related morbidity is often profound. Alternative forms of therapy have not yet achieved the high rates of remission induction and successful maintenance that have been reported with daily cyclophosphamide treatment. Despite continued therapeutic success with cyclophosphamide, our long-term follow-up of patients with Wegener granulomatosis has led to increasing concerns about toxicity resulting from prolonged cyclophosphamide therapy and has encouraged investigation of other therapeutic regimens.     

CYCLOPHOSPHAMIDE THERAPY IN ADULTS WITH MINIMAL-CHANGE NEPHROTIC SYNDROME

Ten adults with minimal-change nephrotic syndrome, eight of whom had failed to respond satisfactorily to steroid therapy, have been treated with cyclophosphamide. Eight patients are now in remission with protein-free urine 2-46 months after withdrawal of all treatment. The remaining two patients have had a partial remission. The only serious side-effect was permanent secondary amenorrhoœa in a 31-year-old woman treated with cyclophosphamide for 20 months. It is suggested that cyclophosphamide should be tried in any adult with minimal-change nephrotic syndrome who does not respond to prednisone within 2 months.     

Immunosuppressive therapy in patients with thyroid eye disease: an overview of current concepts

Thyroid eye disease (TED) is a debilitating disease impairing the quality of life of affected patients. Treatment is often not satisfactory. This review summarizes the existing literature and discusses the most widely used forms of treatment for TED such as glucocorticoids (GCs), and other immunosuppressive agents. GCs are the most commonly used treatment in patients with TED. Other immunosuppressive agents such as cyclosporin A, azathioprin, cyclophosphamide and ciamexone have been used, but the results are modest at best and indicate an unfavorable benefit-risk relationship. Limited experience indicates that methotrexate may be effective even in patients with refractory TED. Somatostatin analogs, octreotide and lanreotide, may provide a valuable, although costly, therapeutic alternative to GCs. Orbital radiotherapy has been used in the management of TED for almost 60 years. However, its beneficial effects have been questioned recently by several studies, the details of which have not yet been published. Other studies have argued in favor of orbital radiotherapy; however, the benefits appear to be limited to improvement of extraocular muscle dysfunction.     

Immunoproliferative small intestinal disease in Greece: presentation of 13 cases including two from Albania

OBJECTIVES: Immunoproliferative small intestinal disease (IPSID) represents a spectrum of clinicopathological entities including alpha-chain disease and other types of lymphoplasmacytic proliferations of the lamina propria of the small intestine, presenting with severe malabsorption. IPSID has been described mainly in the Mediterranean, Middle East, and African countries. It occurs rarely in western countries. We present here our experience from Greece describing some interesting findings in cases diagnosed during the years 1970-2002. METHODS: Current immunological and immunohistochemical methods for the detection of alpha heavy chains and the presence of clonality have been used to study 13 cases of IPSID diagnosed in Greece, two of whom were Albanian residents. RESULTS: The patients were categorized in three subgroups of IPSID: alpha-chain disease (n=8), non-alpha chain disease with other monoclonal immunoglobulins (n=3), and polyclonal 'non-malignant' IPSID (n=2). In several patients the disease had unusual features, and this in some cases delayed the diagnosis. In suspected cases it is thus of the utmost importance to proceed to an exploratory laparatomy. Patients with stage C disease had a short survival, whereas two patients with stage A alpha-chain disease responded to treatment with cyclophosphamide, vincristine and prednisolone, and cyclophosphamide, doxorubicine, vincristine and prednisolone, respectively, have a disease-free long survival of 35 and 12 years, and appear to be cured.     

Rituximab for autoimmune haemophilia: a proposed treatment algorithm

We previously reported durable complete responses following brief courses of rituximab and prednisone with or without cyclophosphamide in four patients with autoimmune haemophilia and inhibitor titres of 5-60 BU. We report here responses to this monoclonal anti-CD20 antibody in four additional patients, including two patients with inhibitor titres >200 BU. Factor VIII levels became normal 2-35weeks after 4 or 8 weekly doses of rituximab, brief courses of prednisone and in one patient immunoglobulin. Complete responses are ongoing at 10 months in two patients. Two patients relapsed: a patient whose initial inhibitor titre was 525 BU relapsed at 3.5 months and a long-term prednisone-dependent patient at 8.5 months. Both responded to second courses of rituximab and prednisone and are in remission. Our experience suggests that rituximab is a safe and effective addition to immunosuppression with prednisone and cyclophosphamide to treat autoimmune haemophilia, and may permit early discontinuation or even avoidance of these potentially toxic agents. High-titre inhibitor patients, however, may require multiple courses of rituximab or the addition of cyclophosphamide. Pending randomized studies, we propose an algorithm based on our experience and other reports for incorporating rituximab in the treatment of this rare disorder.     

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.     

Studies of immunosuppressive drugs in the treatment of lupus nephritis

Long-term, controlled trials to evaluate the efficacy and toxicities of immunosuppressive drug therapies compared to treatment with corticosteroids alone in the management of patients with lupus nephritis have been performed. The studies demonstrate that immunosuppressive drug regimens, particularly intravenous cyclophosphamide, reduce the likelihood of end-stage renal failure. However, toxicities such as herpes zoster and ovarian failure were found to be increased in patients with cyclophosphamide.     

Prolonged 18FDG-PET negative complete remission in a heavily pretreated, elderly patient with diffuse large B cell lymphoma treated with lenalidomide, low dose dexamethasone, and colony stimulating factor (Rd-G)

Diffuse large B-cell lymphoma (DLBCL) is a common lymphoid malignancy among adults in the developed world and accounts for about a third of all patients newly diagnosed with non-Hodgkin lymphoma each year. The prognosis of patients with DLBCL has improved over the past 10 years since the advent of chemoimmunotherapy regimens such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). However, a significant number of patients still experience disease relapse or progression after first or second line therapy, and ~40% of patients will die within 5 years. In particular, elderly patients and those ineligible for high-dose chemotherapy due to comorbidities require effective salvage treatment options with favorable toxicity profile. Several novel therapeutic approaches have been proposed for these patients including monoclonal antibodies, radioimmunotherapy, proteasome inhibitors, mTOR inhibitors, and the immunomodulatory drugs such as thalidomide and lenalidomide.     

Successful treatment of rheumatoid vasculitis-associated foot drop with rituximab

SIR, B-lymphocyte depletion with rituximab, either alone orin combination with cyclophosphamide or methotrexate, has beenshown to have efficacy in rheumatoid arthritis [1]. Rituximabhas also been used as an alternative agent for anti-neutrophilcytoplasmic antibody (ANCA)-positive vasculitis [2, 3] and forgiant cell arteritis [4]. We report our experience in usingrepeated courses of rituximab in a patient with     

Staging and therapy of chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease. Some patients require no therapy and have prolonged survival. Others have brief survival despite intensive treatment. Several staging systems have been developed. These are useful in predicting outcome and need of therapy, but controversies exist. Additional prognostic factors have been identified such as cytogenetics, lymphocyte levels or doubling time, bone marrow morphology, and others. Patients with low-stage CLL have not been shown to benefit from treatment. In patients with intermediate disease, combination chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP) has not been shown to be superior to chlorambucil with or without prednisone. The therapy of high stage CLL is controversial; therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) may be superior to CVP. Future directions of therapeutic research include the treatment of patients with low stage disease, more precise identification of patients requiring therapy, and more precise definition of therapeutic response.     

Allogeneic marrow transplantation in the treatment of preleukemia

Ten patients with preleukemia and life-threatening pancytopenia were treated with marrow transplantation. In all ten cases allogeneic marrow was successfully engrafted. In three patients prepared for transplantation with cyclophosphamide alone, the abnormal cell clone either persisted or reemerged within 6 months of transplantation. The other seven patients were treated with cyclophosphamide plus total body irradiation before transplantation and six of the seven are alive and well without evidence of disease from 7 to 25 months after transplantation. These results suggest that cyclophosphamide alone before marrow transplantation is incapable of eradicating the abnormal clone. Cyclophosphamide combined with total body irradiation appears more effective, although more time is needed for full evaluation of results. This experience also emphasizes the importance of performing chromosome studies before transplantation for pancytopenic states in order to identify cases of preleukemia.