Systemic Wegener's Granulomatosis Research Articles

Idiopathic granulomatous mastitis: a medical or surgical disease of the breast?

Idiopathic granulomatous mastitis (IGM) is a rare benign breast disease, which can be protracted, disfiguring and may be linked to an underlying autoimmune disorder. The clinical presentation may mimic bacterial mastitis or carcinoma. To review the mode of presentation, diagnosis, management, resolution and incidence of IGM in three tertiary breast centres and propose guidelines for management. The breast and anatomical databases of three centres were reviewed from January 2000 to December 2013 to identify patients with histological diagnosis of IGM. Clinical and demographic characteristics were retrieved and treatment modalities and time to resolution were recorded. Seventeen patients were identified with a median age of 40. The majority of patients were premenopausal, multiparous and presented with a mass. All patients had initial treatment as infectious mastitis. The diagnosis was made by core biopsy in 71%. Eleven patients required immunosuppressive treatment with steroids and four of these patients required a steroid-sparing agent because of steroidal side effects, recurrence or persistence of symptoms. The median time to resolution was 3 months (0-24 months). One patient had subsequent systemic Wegener's granulomatosis diagnosed. Idiopathic granulomatosis mastitis requires histological confirmation, close monitoring, exclusion of underlying systemic autoimmune conditions and judicious use of steroids and steroid-sparing agents such as methotrexate. It has a protracted course with some patients relapsing quickly upon cessation of steroids.

Primär kutane Manifestation einer Wegener-Granulomatose

A 57-year-old man was admitted with hemorrhagic papules and necrotising nodules on both elbows and upper legs. Recurrent arthralgia occurred.The skin biopsy showed a cutaneous necrotising vasculitis. Positive test results for c-ANCA and proteinase 3 antibodies and a slightly increased WBC and a mild proteinuria were noticeable.The diagnosis of an early systemic Wegener's granulomatosis was based on elevated proteinase 3-titres and cutaneous histologic findings as necrotising vasculitis and granulomatous inflammation. Treatment with prednisolone followed by methotrexate resolved the cutaneous symptoms and the arthralgia completely. Three months later the patient developed a progredient methotrexate toxicity caused by a glomerulonephritis.Wegener's granulomatosis should be considered if a cutaneous necrotising vasculitis is diagnosed. A cutaneous manifestation could be an early symptom. Methotrexate could be used for treatment of mild courses of Wegener's disease without renal involvement.

Traitement des vascularites systémiques associées aux ANCA

Key points Treatment for ANCA-associated vasculitides is now well defined, but must be ajusted for each patient according to the type of vasculitis, its precise form (e.g., limited versus systemic Wegener's granulomatosis) and severity, and patients' characteristics, such as age and renal function. The therapeutic decision must also take into account the risk of adverse events inherent to each treatment. The efficacy of adequate induction treatment has been demonstrated: more than 80% of patients now achieve remission. Relapse rates nonetheless remain high, especially in Wegener's granulomatosis. Patients with microscopic polyangiitis or Churg-Strauss syndrome with no poor prognostic factors can be treated with corticosteroids alone, with immunosuppressants added only in case of treatment failure. Patients with Wegener's granulomatosis or microscopic polyangiitis or Churg-Strauss syndrome and one or more poor prognostic factors must receive a combination of corticosteroids and immunosuppressants, mainly intravenous pulsed cyclophosphamide. Plasma exchange is indicated as an adjuvant therapy for patients with severe renal involvement. Once remission is achieved, maintenance therapy can replace cyclophosphamide by a less toxic immunosuppressive drug, such as azathioprine or methotrexate. For these latter patients, the optimal duration of induction therapy remains to be determined, but should not be shorter than 18 months. Conversely, there is no need to prescribe high-dose corticosteroids for months. Prednisone must be started at 1 mg/kg/d then rapidly tapered so that patients are not receiving more than 15 mg/d after 3-4 months of therapy. Biological therapies also appear to have a place in the therapeutic armamentarium for ANCA-associated systemic vasculitides, at least for patients whose disease is refractory to conventional therapy. However, the precise indications for anti-TNFα or anti-CD20 monoclonal antibodies and their optimal regimens (doses and durations) have not yet been defined. Anti-IL5, interferon-α and anti-IgE monoclonal antibodies might also be useful for Churg-Strauss syndrome. These biologics must be prescribed extremely cautiously and only in trial settings, especially in view of the adverse effects, few but severe, recently been reported with them.

Classification des vascularites systémiques

Vasculitides are defined by inflammation of blood vessel walls leading to vascular stenosis or occlusion, with various degrees of fibrinoid necrosis of the media and inflammatory infiltration, mainly neutrophilic and sometimes granulomatous. Various classifications of the vasculitides have been proposed. The classifications used most today are the 1990 American College of Rheumatology classification and the Chapel Hill nomenclature, published in 1994 . Only the latter distinguished between polyarteritis nodosa and microscopic polyangiitis and stressed the importance of antineutrophil cytoplasm autoantibodies (ANCA). In practice, primary systemic vasculitides are classified according to their clinical presentations, their precise histological features, and the size of the predominantly affected vessels. Some small-vessel vasculitides are associated with the presence of ANCA: 90% of patients with systemic Wegener's granulomatosis (mainly ANCA with cytoplasm labeling on indirect immunofluorescence and proteinase 3 specificity), 80% of the subjects with microscopic polyangiitis (mostly pANCA with myeloperoxidase specificity), and more than one third of those with Churg-Strauss syndrome (mostly pANCA).

Autoantibodies to neutrophil cytoplasmic antigens (ANCA) do not bind to polymorphonuclear neutrophils in blood

Autoantibodies to neutrophil cytoplasmic antigens (ANCA), particularly to proteinase 3 (PR3), are found in the majority of patients with systemic Wegener's granulomatosis. The autoantibodies are widely used as diagnostic markers. Their role in the development and progression of the disease, however, is still under investigation. The primary target of ANCA, PR3, is located in the cytoplasm of polymorphonuclear neutrophils (PMN) or monocytes and is translocated to the cell surface upon stimulation. In patients with Wegener's granulomatosis PR3 is up-regulated most prominently during active disease. Despite the fact that both autoantibodies to PR3 and PMN expressing PR3 are present in patients with Wegener's granulomatosis, there is no evidence for binding of the autoantibodies to PMN. The present study was designed to analyze binding characteristics of autoantibodies to PR3 on PMN. PMN of patients with active Wegener's granulomatosis (N= 10) were tested for autoantibody binding. Despite high autoantibody titer and PR3 expression on the PMN, no surface-bound IgG was found on PMN ex vivo. When ANCA-containing plasma from patients was incubated with isolated PMN, stimulated to express PR3, again no specific binding of the autoantibody could be detected. Also keeping the samples on ice did not allow surface detection of IgG, ruling out degradation or internalization of the autoantibodies. Only when purified IgG fractions were used, binding to PMN was seen in 14 of 25 patients. Already 1% of plasma, however, was sufficient to greatly reduce the IgG binding. Reduced binding of the IgG fraction was also seen when a larger reaction volume was used. Our data indicate that autoantibodies to PR3 have a rather low affinity for surface-associated PR3 on PMN. This, in turn, argues against the hypothesis that ANCA contributes to the pathogenesis of the disease by stimulating viable PMN in whole blood.

Predicting mortality in systemic Wegener's granulomatosis: a survival analysis based on 93 patients.

To determine predictors of survival of patients with systemic Wegener's granulomatosis (WG). We retrospectively studied 93 patients (median age 52 years, male/female ratio 1.7) with systemic WG. All subjects received cytotoxic drugs. Survival was evaluated as a function of the main clinical and laboratory parameters and 2 disease activity scores assessed at diagnosis. Statistical analyses used the multivariate Cox proportional hazards regression model. The mean followup was 4.5 years; 25 (27%) patients died. According to univariate analysis, a pejorative prognostic value was attributed to serum creatinine >160 micromole/liter (P < 0.001); age >52 years (P < 0.002); absence of ear, nose, and throat (ENT) involvement (P < 0.001); and hemoglobin < or =11.8 gm/dl (P = 0.02). Multivariate analysis retained age >52 years (hazard ratio [HR] = 3.40, P = 0.04) as an independent predictor of poor outcome, whereas the presence of ENT involvement was associated with a longer survival (HR = 0.31, P = 0.02). Our results suggest that an older age and the absence of ENT involvement at diagnosis independently predict an increased risk of mortality for WG patients. These findings could indicate that the prognosis of WG might be governed by the balance between the granulomatosis as opposed to the vasculitic disease process.

A case report of Wegener granulomatosis treated only with corticosteroids for 30 years

Wegener granulomatosis is a systemic vasculitis classically described as involving the upper and lower respiratory tracts together with glomerulonephritis. Its poor prognosis was marginally improved with the use of corticosteroids, and long-term remission was not achieved until the introduction of cytotoxic agents. Generalized or systemic Wegener granulomatosis has a worse prognosis than those limited to the respiratory tracts. To report the case of an individual who we suspect has a 30-year history of Wegener granulomatosis treated only with prednisone. A literature search was performed with PubMed using the keywords Wegener granulomatosis, survival, prognosis, and treatment. Our patient is alive 32 years after her initial symptoms of vasculitis. She has been taking daily prednisone only for the majority of this time. Our clinical diagnosis of Wegener granulomatosis is based on the history and very high antineutrophil cytoplasmic antibody with the cytoplasmic pattern. There may be variants of generalized Wegener granulomatosis that survive with less aggressive treatment.

Sublingual gland involvement in systemic Wegener's granulomatosis: a case report

Wegener's granulomatosis is a systemic vasculitis characterized by necrosis, granulomatosis and inflammation. The usual targets are extra-oral, although salivary gland involvement has been recognized, usually confined to parotid and submandibular glands. A case report is presented of sublingual gland presentation, confirmed on biopsy, which proceeded to systemic involvement. Some evidence suggests that salivary gland involvement, if recognized, may lead to an early diagnosis and the potential for earlier therapeutic intervention.

Long-Term Clinical Course and Histopathologic Scoring in Acute Crescentic Glomerulonephritis

If nontreated or misdiagnosed, acute crescentic glomerulonephritis, clinically defined as rapidly progressive glomerulonephritis (RPGN), may lead to end-stage renal failure (ESRD) within a short time. Histologically, it is characterized by accumulation of inflammatory cells in combination with proliferation of epithelial cells in the glomerulus. According to the proposed immunopathogenic classification by Couser (7), predominantly the immunpathogenic type III without immune deposits often represents the renal manifestation of a systemic vasculitic disease, for example, polyarteriitis or Wegener's granulomatosis. Having investigated 75 patients with acute crescentic glomerulonephritis in respect to their long-term results, we conclude that an early histopathologic diagnosis by using an activity and chronicity score system may not only be a predictor for renal prognosis but also be a valid supposition for differentiated immunosuppressive therapy in supplement to the clinical data on renal function. A therapeutic advantage of a plasmapheresis therapy additionally to the immunosuppressive therapy could not be proven.

Long-term clinical course in acute crescentic glomerulonephritis.

If non-treated or misdiagnosed, acute crescentic glomerulonephritis, clinically defined as rapidly progressive glomerulonephritis (RPGN), may lead to end-stage renal failure (ESRD) within a short time. Histologically, it is characterized by accumulation of inflammatory cells in combination with proliferation of epithelial cells in the glomerulus. According to the proposed immunopathogenic classification by Couser [7], predominantly the immunopathogenic type III without immune deposits often represents the renal manifestation of a systemic vasculitic disease, e.g. polyarteriitis or Wegener's granulomatosis. Having investigated 75 patients with acute crescentic glomerulonephritis for long-term results, we concluded that early histopathologic diagnosis by using an activity and chronicity score system may be not only a predictor for renal prognosis but also a valid supposition for differentiated immunosuppressive therapy in supplement to the clinical data on renal function. The therapeutic advantage of plasmapheresis therapy in addition to immunosuppressive therapy could not be proven.

Immunologic markers for differentiation of autoimmune responses.

Several approaches have been directed at identifying accurate parameters for the measurement of disease activity in autoimmune disorders, both in humans and in experimental animal models. A great deal of previous effort has focused on determining what constitutes antigenic epitopes on various autologous proteins or tissue components, which then can generate an immune response in the host. Much of this work has been clouded by the fact that normal subjects (both animal and human) seem to mount an immune response to myriad autologous proteins, characterized by the formation of antibodies known as natural autoantibodies. During the course of certain autoimmune diseases such as systemic lupus erythematosus (SLE) or Wegener's granulomatosis (WG), patients produce what appear to be autoantibodies reacting with autologous components such as DNA and Sm antigen (SLE) or proteinase-3 (WG). Low levels of these same autoantibodies are present in IgG derived from normal subjects. Recently, we have found that IgG anti-F(ab')2 from normal subjects, affinity-purified from immunoabsorbent columns of human F(ab_)2 Sepharose, exhibits not only anti-F(ab')2 but also anti-dsDNA and anti-Sm activity. These antibodies constitute an average of 0.02% of normal serum IgG. Similar findings have also been observed in SLE patients with active disease. Our findings suggest that perturbation of the idiotypic network may represent an important fundamental aspect of many autoimmune disorders.

Coexistence of Anti-Neutrophil Cytoplasmic Antibody-Associated Glomerulonephritis and Membranous Glomerulopathy

The association of renal Wegener's granulomatosis with other glomerular diseases is very rare. A case of anti-neutrophil cytoplasmic antibody-associated necrotizing glomerulonephritis superimposed on a membranous glomerulopathy in a patient with systemic Wegener's granulomatosis is reported. Renal failure was corrected by immunosuppressive therapy treatment, but a non-nephrotic-range proteinuria persisted for several months. The association of membranous glomerulopathy with anti-glomerular basement membrane disease and other autoimmune diseases is well described; however, anti-neutrophil cytoplasmic antibody-associated vasculitis superimposed on membranous glomerulopathy has not been reported previously.

Diagnosis and management of systemic Wegener's granulomatosis presenting with anterior ocular inflammatory disease.

The ocular and systemic features of 10 patients whose Wegener's granulomatosis presented with corneoscleral inflammatory disease are described. Marginal corneal infiltrates were seen in all patients with anterior scleritis and were a valuable sign of disease activity. Nine out of 10 patients had symptoms of systemic vasculitis on presentation; seven had renal impairment; three had chest x-ray abnormalities. Autoantibodies against neutrophil cytoplasmic determinants (ANCA) were present in all cases. In seven patients the scleritis responded well to pulsed immunosuppressive therapy followed by long term oral steroids and cyclophosphamide. Oral steroid therapy alone failed to control severe disease. Corneoscleral disease was not a cause of visual loss. It is important to realise that inflammatory corneoscleral disease may be the presenting feature of a severe systemic vasculitis.

Ocular Manifestations of Patients With Circulating Antineutrophil Cytoplasmic Antibodies

Antineutrophil cytoplasmic antibodies are seen in patients with systemic vasculitides, especially Wegener's granulomatosis. Antineutrophil cytoplasmic antibodies are helpful laboratory markers for these disease. We report on the ocular findings of six patients with systemic vasculitis who had antineutrophil cytoplasmic antibodies. Four patients had systemic Wegener's granulomatosis, one had microscopic polyarteritis, and in one a specific histopathologic diagnosis could not be made. Two patients were first evaluated for systemic vasculitis because of their ocular manifestations. Ocular findings included ptosis, bilateral lacrimal gland masses, proptosis, choroidal folds, episcleritis, phlebitis, retinal and vitreous hemorrhage, keratitis sicca, and bilateral central scotomas. It was difficult to make a systemic diagnosis in all cases. If systemic vasculitis is in the differential diagnosis of a patient with suggestive ocular findings, antineutrophil cytoplasmic antibody testing should be considered. A prospective study of antineutrophil cytoplasmic antibody testing should be considered in patients with ocular findings that suggest the possibility of vasculitis.

CANCA test and the detection of Wegener's disease in sclerokeratitis and uveitis

Ocular signs and symptoms may be the initial signs of systemic or limited Wegener's granulomatosis. The diagnosis is difficult to make on ophthalmic manifestations alone, because clinical and histopathological markers are not specific enough. By means of the cANCA serum test it is possible to make the diagnosis in an early stage and to prevent more disastrous complications. The relation of cANCA titre and the clinical and histopathological findings of five patients with an acute or chronic Wegener's granulomatosis are discussed.

Twenty-five years of immunosuppression.

Two unrelated discoveries that were made 25 years ago have brought about important and convergent changes in medical immunology. The first was the occurrence of antinuclear antibodies in systemic lupus erythematosus (7). It contributed to the beginning of an era of research in the rheumatic diseases that continues with undiminished vigor and productivity. The second was the immuno- suppressive effect of 6-mercaptopurine, an antagonist of purine biosynthesis (-23). It also had an important clinical impact and was soon applied not only to suppress the rejection of human kidney allografts (reviewed in 3) but also to treat refractory cases of autoimmune hemolytic anemia and systemic lupus erythematosus (5). The introduction of chemical immunosuppression in organ grafting has revolutionized medicine, but whether the same can be said for its use in the treatment of autoimmune diseases remains, except in a few instances, an open question. Immunosuppressive therapy with agents like 6-mercaptopurine and its de- rivative, azathioprine, and cyclophosphamide is now so well known a topic that nothing useful can be added to the already overburdened literature except with regard to the chronic toxicity of these agents. Only after years of experience ha~ it become evident that immunosuppressive drugs have late effects of great concern. The situation with cyclophosphamide and other alkylating agents (e. g., chloram- bucil) is clear. They are leukemogenic in humans and the sustained use of these compounds in patients with nonmalignant disease carries a risk of acute myelo- genous leukemia (16). The degree of risk is unknown but it may be as high as 15~o. For that reason, prudence is required in the use of alkylating drugs as immunosup- pressants and they should be avoided in children unless there are compelling reasons to do otherwise. A new twist to the problem of the long-term risk of alkylating agents is now coming to the attention of many physicians. It can be seen in the patient with systemic lupus erythematosus or Wegener's granulomatosis who, as a result of 2 or 3 years of treatment with cyclophosphamide, enters a solid remission and finally seems cured. After 5 to 10 years, however, the disease recurs. Should that patient

Psychologic and Nenrologic Manifestations of Systemic Wegener's Granulomatosis

Psychologic and Nenrologic Manifestations of Systemic Wegener's Granulomatosis