Search

Background: Antineutrophil cytoplasmic antibody-associated vasculitides (AAV) is a group of systemic necrotizing small vessel autoimmune diseases, with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) being the two most common. The co-existence of AAV with different immune-mediated diseases (autoimmune disesases - AID) might affect the clinical presentation of the primary disease. The purpose of the study was to assess the co-existence of AAV with AID and to investigate whether it affects the characteristics and the course of AAV., Methods: A retrospective single-center study was performed to identify patients with a diagnosis of MPA or GPA and concomitant AID, and to investigate their clinical features and characteristics. The group consisted of consecutive unselected AAV patients treated at a large university-based hospital, since 1988 with follow-up until 2022., Results: Among 284 patients diagnosed either with GPA (232) or MPA (52), 40 (14,1%) had co-existing AIDs. The most frequent were: Hashimoto thyroiditis (16 cases), rheumatoid arthritis (8 cases), followed by psoriasis (6 cases), pernicious anemia (3 cases), and alopecia (3 cases). Patients with autoimmune comorbidities had a significantly longer time between the onset of symptoms and the diagnosis (26 vs. 11 months, p < 0.001). Laryngeal involvement (20.0% vs. 9.0%, p = 0,05), peripheral nervous system disorders (35.0% vs. 13.9%, p < 0.001), and neoplasms (20.0% vs. 8.6%, p = 0,044) were more common in patients with AID comorbidities, compared to subjects without AID. In contrast, renal involvement (45.0% vs. 70.9%, p = 0.001) and nodular lung lesions (27.5% vs. 47.5%, p = 0.044) were significantly less frequent in patients with co-morbidities. Following EUVAS criteria, patients with autoimmune co-morbidities had a generalized form of the disease without organ involvement (52.5% vs. 27.2%, p = 0.007), while the others had a higher percentage of generalized form with organ involvement (38.3% vs. 20.0%, p = 0.007)., Conclusions: The coexistence of AAV with different autoimmune diseases is not common, but it might affect the clinical course of the disease. Polyautoimmunity prolonged the time to diagnosis, but the AAV course seemed to be milder. Particular attention should be paid to the increased risk of cancer in these patients. It also seems reasonable that AAV patients should receive a serological screening to exclude the development of overlapping diseases., (© 2024. The Author(s).)

Objectives/hypothesis: We sought to characterize rates of progression to posterior glottic stenosis (PGS) from autoimmune or idiopathic subglottic stenosis., Study Design: This was a retrospective review., Methods: Patients from a tertiary-care laryngology practice over a 10-year period with autoimmune or idiopathic subglottic stenosis (SGS) were included. Patients with a history of prolonged intubation or other causes of iatrogenic stenosis were excluded. PGS was confirmed on videostrobolaryngoscopy recordings by a fellowship-trained laryngologist. PGS type (1-4) was also recorded. Demographic information was recorded, and if applicable, autoimmune disease type was specified. Time until PGS was recorded along with the number of interventions. Chi-squared analysis was used to compare PGS in autoimmune and idiopathic SGS., Results: A total of 77 patients were identified with autoimmune (32 patients) or idiopathic (45 patients) subglottic stenosis. Autoimmune pathologies included systemic lupus erythematosus, granulomatosis with polyangiitis (GPA), rheumatoid arthritis, relapsing polychondritis, and sarcoidosis, with GPA the most common (14/32). Patients with autoimmune SGS had a higher rate of PGS (10 of 32) compared to idiopathic subglottic stenosis (1 of 45) for an odds ratio of 20 (95% CI: 2.4-166.4, P = .006). Patients with idiopathic SGS were more likely to be female (all 45 compared to 29/32 autoimmune, P = .07) and older (mean 53 (range 29-75) compared to 46 (20-82), P = .02)., Conclusions: In this large patient cohort, autoimmune SGS patients were found to have a higher likelihood of developing PGS compared to their idiopathic counterparts, suggesting that counseling for this progression may be warranted., Level of Evidence: 4 Laryngoscope, 131:1816-1820, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Neutrophils are critical in the defense against bacterial and fungal pathogens, and they also modulate the inflammatory process. The areas where neutrophils are studied have expanded from the restricted field of antibacterial defense to the modulation of inflammation and finally, to fine-tuning immune responses. As a result, recent studies have shown that neutrophils are implicated in several systemic autoimmune diseases, although exactly how neutrophils contribute to these diseases and the molecular mechanisms responsible are still under investigation. In a group of autoimmune vasculitides associated with anti-neutrophil cytoplasmic antibodies (AAVs), granulomatosis with polyangiitis (GPA) illustrates the concept that autoimmunity can develop against one specific neutrophil protein, namely, proteinase 3 (PR3), one of the four serine protease homologs contained within azurophilic granules. In this review, we will focus on recent molecular analyses combined with functional studies that provide clear evidence that the pathogenic properties of PR3 are not only a result of its enzymatic activity but also mediated by a particular structural element-the hydrophobic patch-which facilitates associations with various proteins and lipids and permits anchorage into the plasma membrane. Furthermore, these unique structural and functional characteristics of PR3 might be key contributors to the systemic inflammation and to the immune dysregulation observed in GPA., (© Society for Leukocyte Biology.)

Autoimmune origin ranks fifth in the etiologic classification of laryngotracheal stenosis. Wegener's disease is the autoimmune illness most associated with stenosis; however, there are other autoimmune diseases that may also be associated with it. A descriptive, retrospective study of 9 cases of laryngotracheal stenosis associated with autoimmune disease was carried out. There were 9 patients (8 females and 1 male) with an average age of 27.9 years. Four of the patients suffered from Wegener's disease, 1 from ulcerative colitis and 1 from purple vasculitis. The other 3 patients only had positive c-ANA. Endoscopic treatment was performed in 3 cases. The other 6 patients required open surgery. Respiratory results were acceptable. Based on our study, we feel that the immunological profiles should be studied in all patients with stenosis, given that not only Wegener's disease is linked to stenosis., (Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. All rights reserved.)

Objective: Patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and granulomatosis with polyangiitis (Wegener's) (GPA) have a 3-20-fold increased risk of herpes zoster compared to the general population. The aim of this study was to evaluate if susceptibility is due to decreased levels of cellular and/or humoral immunity to the varicella-zoster virus (VZV)., Methods: A cross-sectional study of VZV-specific immunity was performed in 38 SLE patients, 33 GPA patients, and 51 healthy controls. Levels of IgG and IgM antibodies to VZV were measured using an in-house glycoprotein enzyme-linked immunosorbent assay (ELISA). Cellular responses to VZV were determined by interferon-γ (IFNγ) enzyme-linked immunospot (ELISpot) assay and carboxyfluorescein succinimidyl ester (CFSE) dye dilution proliferation assay., Results: Levels of IgG antibodies to VZV were increased in SLE patients as compared to healthy controls, but levels of IgM antibodies to VZV were not. Antibody levels in GPA patients did not differ significantly from levels in healthy controls. In response to stimulation with VZV, decreased numbers of IFNγ spot-forming cells were found among SLE patients (although not GPA patients) as compared to healthy controls. Proliferation of CD4+ T cells in response to stimulation with VZV was decreased in SLE patients but not GPA patients., Conclusion: SLE patients have increased levels of IgG antibodies against VZV, while cellular immunity is decreased. In GPA patients, antibody levels as well as cellular responses to VZV were comparable to those in healthy controls. These data suggest that increased prevalence of herpes zoster in SLE patients is due to a poor cellular response. Vaccination strategies should aim to boost cellular immunity against VZV., (Copyright © 2014 by the American College of Rheumatology.)

Protein glycosylation is one of the most common post-translational modifications, involved in the well described protein biosynthesis process. Protein glycosylation seems to play a major role in the pathogenesis of auto-immune diseases. Herein are described the main alterations of autoantibody glycosylation associated with autoimmunes diseases such as rheumatoid arthritis, IgA glomerulonephritis, Schoenlein-Henoch purpura, Sjögren's syndrome, systemic scleroderma, systemic lupus erythematosus, myasthenia gravis and granulomatosis with polyangiitis (Wegener). Molecular identification of altered immunoglobulin glycosylation could lead to a better understanding of the pathogenesis of those diseases, might allow an evaluation of their biological activity and could even be a new therapeutic target., (Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Wegener's granulomatosis (WG) is a life-threatening autoimmune vasculitis that affects lungs, kidneys and other organs. A hallmark of WG is the presence of classic anti-neutrophil cytoplasmic antibodies (c-ANCA) against self-proteinase 3 (PR3). Little is known about the role of these antibodies and PR3-specific immune responses in disease development. In this study, we demonstrate that PR3-specific autoimmune responses are pathogenic in non-obese diabetic (NOD) mice with an impaired regulatory arm of the immune response. Immunization of autoimmunity prone NOD mice with rmPR3 (recombinant mouse PR3) in complete Freund's adjuvant (CFA) resulted in high levels of c-ANCA, without detectable disease development. However, when splenocytes from these immunized mice were transferred into immunodeficient NOD-severe combined immunodeficiency (SCID) mice, the recipient mice developed vasculitis and severe segmental and necrotizing glomerulonephritis. No disease developed in NOD-SCID mice that received splenocytes from the CFA-alone-immunized donors (controls), indicating that disease development depends upon PR3-specific immune responses. In contrast to the pathology observed in NOD-SCID mice, no disease was observed when splenocytes from rmPR3-immunized C57BL/6 mice were transferred into immunodeficient C57BL/6-RAG-1(-/-) mice, suggesting that complex and probably multi-genetic factors play a role in the regulation of disease development.

Background: The neutrophilic dermatoses comprise a group of cutaneous disorders that are characterized histopathologically by infiltration of the dermis with mature neutrophils with or without vessel wall destruction. Neutrophilic dermatoses have been reported in association with a variety of autoimmune diseases, most recently as a manifestation of lupus erythematosus., Observations: We describe 2 patients with photodistributed violaceous plaques: one with associated heliotrope rash and malar erythema, and the other with scalp involvement and Gottron-like papules. In each case, the biopsy specimen revealed changes compatible with a neutrophilic dermatosis as opposed to an interface dermatitis. The first patient also had a history of Graves disease and primary biliary cirrhosis, while second patient had Wegener granulomatosis. The 2 patients responded to therapy with oral dapsone and prednisone, respectively., Conclusions: The atypical presentation of neutrophilic dermatosis in 2 patients with clinical features of dermatomyositis and intercurrent autoimmune-mediated illnesses may suggest an expansion in the clinical spectrum of parainflammatory neutrophilic dermatoses. The finding of a neutrophilic dermatosis in a biopsy specimen from a patient without a classic clinical presentation should invoke a thoughtful search for underlying immune complex-mediated systemic disease.

Persistent T cell activation is a common finding in anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated systemic vasculitis (AAV) patients. Because imatinib, a selective inhibitor of the ABL, ARG, PDGFR and c-KIT tyrosine kinases, inhibits T cell activation, this study was conducted to evaluate the potential use of imatinib for the treatment AAV patients refractory to conventional therapy. In particular, we investigated the inhibition of T cell activation by this drug and its efficacy on activated T cells from anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated systemic vasculitides (AASV) patients. T cell stimulation has been induced by anti-CD3/anti-CD28 antibodies or by phorbol myristate acetate (PMA)/ionomycin. T cell proliferation was analysed by tritiumthymidine incorporation. Cell cycle progression was determined by propidium iodide staining using fluorescence activated cell sorter (FACS) analysis and by RNAse protection assay (RPA). Cytokine levels were assessed by enzyme-linked immunosorbent assay. T cell proliferation was inhibited significantly by imatinib, due most probably to cell cycle arrest in the G1-phase. This was paralleled by inhibition in the expression of cyclin-dependent kinases 1 and 2 mRNA. The expression of CD25 in naive and memory T cells was decreased significantly by imatinib in activated T cells. Similarly, conversion from naive to memory T cells after T cell activation was impaired by imatinib. Imatinib did not influence interleukin-2 and tumour necrosis factor-alpha production but increased interferon-gamma production. These observed effects of imatinib were similar in T cells from AASV patients and from healthy individuals. Imatinib might be an alternative therapeutical option for AASV patients refractory to conventional therapy.

Maintenance of immune tolerance in the periphery can be envisioned as a balance between autoreactive lymphocytes and regulatory mechanisms that counteract them. The naturally occurring CD4(+)CD25(+) regulatory T cells (T(REGs)) have a major role in modulating the activity of self-reactive cells. The identification of Forkhead box P3 transcription factor (FoxP3) as the critical determinant of T(REG) development and function has provided new opportunities and generated expanded interest in studying the balance between autoimmunity and regulatory mechanisms in human autoimmune diseases. The identification of both human and mouse diseases resulting from the lack of FoxP3 expression, and consequently the absence of T(REGs), has rapidly expanded knowledge of T(REG) development and function during the past 5 years. Although it is still unclear how these regulatory cells function, they can inhibit the activation of potentially pathogenic T cells in vitro. Using in vitro functional assays and phenotypic analysis, T(REGs) isolated from patients with a variety of autoimmune diseases have been shown to exhibit reduced regulatory function as compared with those isolated from healthy controls. This Review will focus on the current state of knowledge on human T(REGs) and their association with specific autoimmune diseases.

Objective: Rituximab, a chimeric anti-CD20 monoclonal antibody, has been shown to be quite effective in the treatment of immune disorders resulting from autoantibodies. We prospectively studied the long-term effects of rituximab in 10 patients with anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis refractory to conventional therapy (n=3) or in second or subsequent relapse (n=7)., Methods: The median age of patients was 53 yrs (range 38-70 yrs). Eight were classified as Wegener's granulomatosis, and two as microscopic polyangiitis. Clinical activity was assessed using the Birmingham Vasculitis Activity Score modification for Wegener's granulomatosis. Treatment consisted of intravenous infusions of rituximab given at the dose of 375 mg/m2 weekly for four consecutive weeks., Results: All patients experienced a rapid clinical improvement following the administration of rituximab, with nine complete responses and one partial response at 6 months. With a median follow-up of 33.5 months (range 26-45 months), three patients have thus far relapsed. Retreatment with the monoclonal antibody at the same dose and schedule resulted in a new sustained response in all these patients. Rituximab therapy resulted in prolonged B-cell depletion. The ANCA titres decreased significantly in all patients, with eight out of 10 becoming ANCA-negative and three remaining ANCA-negative even after B-cell recovery. Infusion-related side effects were observed in one patient, but were of mild intensity and did not require discontinuation of treatment., Conclusions: Rituximab is an effective and well-tolerated treatment for patients with ANCA-associated vasculitis and should be strongly considered in severely affected patients who do not respond to standard therapy or in those in whom cytotoxic therapy bears a high risk of morbidity.

Wegener's granulomatosis (WG) is a complex autoimmune syndrome that is characterised by upper/lower respiratory necrotising granulomatosis, glomerulonephritis and small-vessel vasculitis. Since Wegener's 1936 description, considerable advances in recognition and treatment have changed this disease from a rapidly and uniformly fatal illness to a chronic disease characterised by remissions and relapses. The serendipitous discovery of anti-neutrophil cytoplasmic antibodies (ANCAs) as a marker associated with WG focused attention on the potential pathogenic role of these antibodies and has recently led to the development of novel animal models that might facilitate our understanding of the disease pathogenesis. Future animal models of this disease will have to account for the role of both ANCA-mediated pathology and granulomatous inflammation to enable us to understand the chronic and persistent features of WG in humans.

Objective: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides are increasingly recognized in older patients. However, it is unknown whether disease presentation and response to treatment differs from younger patients. We aimed to examine the presentation, response to treatment and outcome of patients over 65 yr of age compared with a younger cohort., Methods: This retrospective, single centre, sequential cohort study reports presenting features and outcome of 233 consecutive new patients with ANCA-associated vasculitis between 1990 and 2000., Results: The median age of all patients was 65 yr (range 16-90 yr). Older patients (>65 yr) presented with more severe renal involvement at presentation (P < 0.001). Older patients were as likely to respond to treatment or undergo relapse as the younger patients. Older patients receiving immunosuppression had an increased risk of infection (P = 0.0027). Survival was worse in the older group (P = 0.016) and death occurred early. Mortality was associated with poor renal function (creatinine >400 micromol/l), infection and low serum albumin. Leucopenia was associated with severe renal impairment (P = 0.0048) and increased risk of infection (P = 0.0006). Multivariate analysis determined that serum creatinine >400 micromol/l and age were independent risk factors for poor prognosis., Conclusion: ANCA-associated vasculitis occurs frequently in older patients and physicians should maintain a high index of suspicion. Older patients have a poorer prognosis due to more severe renal involvement and increased sensitivity to adverse effects of treatment. This study highlights the importance of careful dosing of cyclophosphamide: in those aged over 65 yr a 25% dose reduction is safe and reduces the risk of leucopenia. This study further highlights the importance of renal function on prognosis and the need for less toxic treatment regimens.

Clinical and serological profiles of idiopathic and drug-induced autoimmune diseases can be very similar. We compared data from idiopathic and antithyroid drug (ATD)-induced antineutrophil cytoplasmic antibody (ANCA)-positive patients. From 1993 to 2003, 2474 patients were tested for ANCA in the Laboratory for Allergy and Clinical Immunology in Belgrade. Out of 2474 patients, 72 (2.9%) were anti-proteinase 3 (PR3)- or anti-myeloperoxidase (MPO)-positive and their clinical and serological data were analyzed. The first group consisted of ANCA-associated idiopathic systemic vasculitis (ISV) diagnosed in 56/72 patients: 29 Wegener's granulomatosis (WG), 23 microscopic polyangiitis (MPA) and four Churg-Strauss syndrome. The second group consisted of 16/72 patients who became ANCA-positive during ATD therapy (12 receiving propylthiouracil and four receiving methimazole). We determined ANCA and antinuclear (ANA) antibodies by indirect immunofluorescence; PR3-ANCA, MPO-ANCA, anticardiolipin (aCL) and antihistone antibodies (AHA) by ELISA; and cryoglobulins by precipitation. Complement components C3 and C4, alpha-1 antitrypsin (alpha1 AT) and C reactive protein (CR-P) were measured by nephelometry. Renal lesions were present in 3/16 (18.8%) ATD-treated patients and in 42/56 (75%) ISV patients (p <0.001). Skin lesions occurred in 10/16 (62.5%) ATD-treated patients and 14/56 (25%) ISV patients (p <0.01). ATD-treated patients more frequently had MPO-ANCA, ANA, AHA, aCL, cryoglobulins and low C4 (p <0.01). ISV patients more frequently had low alpha1 AT (p = 0.059) and high CR-P (p <0.001). Of 16 ATD-treated patients, four had drug-induced ANCA vasculitis (three MPA and one WG), while 12 had lupus-like disease (LLD). Of 56 ISV patients, 13 died and eight developed terminal renal failure (TRF). There was no lethality in the ATD-treated group, but 1/16 with methimazole-induced MPA developed pulmonary-renal syndrome with progression to TRF. ANCA-positive ISV had a more severe course in comparison with ATD-induced ANCA-positive diseases. Clinically and serologically ANCA-positive ATD-treated patients can be divided into two groups: the first consisting of patients with drug-induced WG or MPA which resemble ISV and the second consisting of patients with LLD. Different serological profiles could help in the differential diagnosis and adequate therapeutic approach to ANCA-positive ATD-treated patients with symptoms of systemic disease.

Objective: In the light of previous reports of an association between malignancy and renal vasculitis, we aimed to investigate the association of malignancy in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, either Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA), and compare it with the general population and disease control groups comprising patients with systemic lupus erythematosus (SLE) or Henoch-Schonlein purpura (HSP)., Methods: A retrospective review of 200 consecutive patients with WG or MPA was performed. Malignancies preceding or concurrent with vasculitis were recorded and the incidence of malignancy was compared with those in a population of 129 patients with HSP, 333 patients with SLE and a normal population in the West Midlands of the UK., Results: Twenty patients had a diagnosis of malignancy, 14 had MPA and six had WG. Patients with ANCA-associated vasculitis had an increased risk of malignancy compared with HSP patients, of whom six patients had malignancy (relative risk 0.85, confidence interval 0.69-1.05; P = 0.034), or SLE patients, of whom five patients had malignancy (relative risk 0.31, 95% confidence interval 0.14-0.7; P<0.0001). The rate of malignancy compared with an age-matched control group was increased in patients with ANCA-associated vasculitis and HSP (ANCA-associated vasculitis, relative risk 6.02, 95% confidence interval 3.72-9.74; HSP, relative risk 5.25, 95% confidence interval 2.4-11.5). The presence of ANCA was not predictive of malignancy., Conclusion: In conclusion, patients with ANCA-associated vasculitis have an increased risk of preceding or concurrent malignancy.

Background: Endothelial vasomotor dysfunction and markers of systemic inflammation are independent determinants of cardiovascular risk. However, the link between clinical inflammation and endothelial dysfunction is unclear. The aim of this study was to use anti-neutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) as a model of systemic inflammation in which to test the hypothesis that inflammation is associated with endothelial dysfunction and can be reversed with anti-tumor necrosis factor-alpha (TNF-alpha) therapy., Methods and Results: Fourteen patients with active AASV and 21 age-matched control subjects were studied. Endothelial function was assessed through the use of forearm plethysmography and related to clinical disease activity: Birmingham Vasculitis Activity Score (BVAS) and serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), and TNF-alpha. The effects of anti-TNF-alpha therapy (infliximab), either alone (n=6) or in combination with standard treatment (n=4), on endothelial function were subsequently determined. Patients had a mean BVAS of 11+/-1, and CRP and IL-6 were higher in the AASV group than in control subjects (34.8+/-10.5 versus 1.6+/-0.2 pg/mL, P<0.001; 9.0+/-0.7 versus 6.7+/-0.6 pg/mL, P=0.02). Forearm blood flow response to acetylcholine (ACh) was reduced in the patients compared with control subjects (P=0.002), but sodium nitroprusside (SNP) responses were not (P=0.3). The response to ACh improved with infliximab treatment (P=0.004) in particular, with infliximab alone (P=0.03)., Conclusions: AASV is associated with endothelial dysfunction. Anti-TNF-alpha therapy, alone or in combination with standard treatment, results in clinical remission, reduced inflammation, and improved endothelium-dependent vasomotor responses.

Little is known about the etiologies of diseases associated with circulating antineutrophil cytoplasm autoantibodies (ANCA), such as primary vasculitides and inflammatory bowel diseases. However, the understanding of immune mechanisms supposedly involved in the pathogenesis of these diseases is still growing. In the present review, we first focus on the mechanisms triggering the development of ANCA, including the potential role of microbial superantigens and the possible defect(s) in the progression of apoptosis or in the removal of apoptotic cells. We next concentrate on the contribution of ANCA to the clinical symptoms and on the pathogenic role of ANCA, including the accessibility of ANCA antigens as targets for circulating antibodies and the mode of action of ANCA. Mechanisms of neutrophil activation by ANCA include the engagement of Fcgamma receptors, the possible mechanisms of neutrophil-mediated tissue damage, and the neutrophil-endothelial interaction.

Background: Cyclophosphamide has transformed the outcome of ANCA-associated vasculitis, but it is highly toxic. Recent studies have suggested that pulsed intravenous cyclophosphamide (pCyc) is an effective alternative with less complications, but may lead to an increased rate of relapse. However, these studies used relatively short courses of treatment with cyclophosphamide. In this study we used a prolonged course of low-dose intravenous cyclophosphamide for 18-24 months for ANCA-associated vasculitis, evaluated the effectiveness of pCyc and analysed the outcome of a prolonged treatment on the rate of relapse., Methods: A retrospective analysis of all the patients treated with pCyc from 1995 to 2002 was performed., Results: Thirty-seven patients were followed for an average of 38 months. Thirty-four of 37 patients (91.9%) achieved complete remission at 3 months. Eight (21%) episodes of relapse occurred in 7 patients. The cyclophosphamide was well tolerated with a low rate of infections (18.9%) and 1 death (2.7%) due to sepsis whilst on cyclophosphamide., Conclusion: In this study, pCyc was effective in achieving rapid remission and had a low complication rate. If prolonged, this treatment may reduce the rate of relapse., (Copyright 2004 S. Karger AG, Basel)

There are several rheumatologic and autoimmune disorders that can masquerade as allergic disease. Identification of these conditions in an office setting can be a challenge for the practicing allergist-immunologist. These conditions include rheumatoid and juvenile arthritis, Sjogren's syndrome, systemic lupus erythematosus, Behcet's and antiphospholipid syndromes, systemic sclerosis, vasculitis, sarcoidosis, chronic fatigue syndrome, and fibromyalgia. The article will address these topics and include clinical uses of immunologic tests for diagnosis.

Systemic autoimmune diseases form a diverse group which includes: systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), scleroderma, dermato-polymyositis, Wegener's granulomatosis, Sjögren syndrome. Although multisystem involvement is the hallmark of these diseases, the heart seems to be less affected than other organ systems. The aim of the study was to study possible cardiac abnormalities in patients with documented systemic autoimmune diseases and to assess whether there was any relation between antiphospholipid, anti-dsDNA antibodies and myocardial dysfunction findings. 76 patients (53 with SLE, 9 with MCTD, 8 with scleroderma, 6 with Wegener's granulomatosis) were subjected to our study, 69% of these patients manifested cardiac involvement, based on two-dimentional echocardiografic examination (36%--post-inflammatory valvular thickening, 20%--pericardial effusions, 15%--valvular regurgitation, 7%--left atrial enlargement, 5%--left ventricular hypertrophy, 4%--left ventricular dysfunction). None of the patients showed characteristic, acute Libman-Sacks endocarditis, which probably can be explained by chronic corticosteroid-treatment. Clinical evidence of cardiac abnormalities has been observed, in as many as 58% of cases with positive echocardiographic findings. The frequency and extend of cardiac pathology positively correlated with the detection of antiphospholipid antibodies. No such relationship was observed in patients with the presence of very high titers of antinuclear antibodies (anti-dsDNA). In conclusion, our results indicate that echocardiography is a useful method for assessment and monitoring cardiac involvement in the systemic autoimmune diseases.

Polymorphisms of human Fc receptors (FcRs) have been described that are associated with the development or progression of autoimmune diseases. The FcR polymorphisms affect the affinity with which FcRs interact with immunoglobulin molecules. Intravenous immunoglobulin is administered as therapy for many autoimmune diseases and might exert its effects by interacting with FcRs. Thus, FcR polymorphisms might influence the efficacy of intravenous immunoglobulin therapy for patients with certain autoimmune diseases. In this article we review FcR polymorphisms in relation to autoimmune diseases for which intravenous immunoglobulin is used therapeutically.

Wegener's granulomatosis is a form of systemic vasculitis of unknown etiology that affects the small blood vessels. The disease is characterized by the formation of granulomas on small and medium blood vessels, and often affects the respiratory tract and renal system. In 86% of diagnosed cases, renal compromise is in the form of glomerulonephritis. Wegener's granulomatosis can occur at any age, principally during the 4th and 5th decades of life, and 85% of cases occur over the age of 19 years. In the United States about 3 per 100,000 cases are reported, with a major occurrence in males. The present report is about a case of a 12 year old female with Wegener's granulomatosis of 18 months of evolution, with symptoms such as epistaxis, generalized edema, cough, dyspnea, hemoptysis, high blood pressure and macroscopic hematuria. Out of the five criteria for the diagnosis of Wegener's granulomatosis, she had perinuclear anti-neutrophil cytoplasmic antibody positive to serum p-ANCA mark, which is the least frequent, which makes more difficult the diagnosis. Over a period of five years, in our hospital, we have diagnosed 11 patients with Wegener's granulomatosis, and the present case is the only pediatric case.

The triad of small vessel vasculitides (SVV) comprise Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CS). All three are associated with presence of circulating IgG antineutrophil cytoplasm antibodies (ANCA) which target autoantigens contained, primarily, within neutrophil azurophilic granules. The widely accepted model of pathogenesis suggests that ANCA activate cytokine-primed neutrophils within the microvasculature, leading to by-stander damage to endothelial cells, and rapid escalation of inflammation with recruitment of mononuclear cells. Activation may be initiated, in vitro, by the coligation of the PR3 or MPO antigen, translocated to the cell surface, and FcgammaRIIa/FcgammaRIIIb receptors. This suggests that the IgG subclass profile of ANCA and, possibly, its glycosylation status could influence the inflammatory mechanisms activated. The glycosylation status of total IgG isolated from the sera of patients with WG (13), MPA (6) and CSS (1) was determined by analysis of the released oligosaccharides. A deficit in IgG galactosylation is demonstrated for all patient samples, compared to controls. The mean percentage values for the agalactosylated (G0) oligosaccharides were 57% (SD +/- 9.71), 47% (SD +/- 4.25) and 28% (SD +/- 4.09) for WG, MPO and control samples, respectively. The G0 levels for polyclonal IgG isolated from the sera of both WG and MPA patients were significantly increased compared to controls (P < 0.0001). The major glycoform present therefore is agalactosylated (G0) IgG. In previous studies the G0 glycoform of IgG has been shown to bind and activate mannan binding lectin, and hence to activate the complement cascade, and to facilitate mannose receptor binding and the uptake of IgG complexes by macrophages and dendritic cells. Both of these activities could impact on the processing and presentation of self-antigens in autoimmune disease.

The genetics of multifactorial diseases characterized by autoimmune phenomena are elusive so far. Yet, it is clear that the genetic contribution to a given clinically defined autoimmune disease entity is mostly variable and highly complex. On the basis of two basically different model diseases, Wegener's Granulomatosis and multiple sclerosis, approaches are discussed to unravel at least certain genetic predisposition factors. Major difficulties in these analyses arise from (in)exact definition of the clinical phenotype (disease entity), the vast number of potential candidate genes, the small to modest contribution of each genetic variation to disease risk and the combinatorial possibilities.

Our experience regarding serum soluble interleukin-2 receptor (sIL-2R) measurement as a marker of lymphocyte activation consists of patients with autoimmune disease: 37 with systemic lupus erythematosus (SLE), 23 with autoimmune hepatitis (AIH), 74 with inflammatory bowel disease and six with Wegener's granulomatosis (WG). The influence of immunosuppressive therapy has also been assessed. Serum sIL-2R in SLE is significantly higher than in healthy controls and good correlation is found between sIL-2R and disease activity. Severity of kidney inflammation in lupus nephritis can be reflected by the increased excretion of sIL-2R. It was found that sIL-2R level significantly falls when the disease becomes clinically inactive after immunosuppressive therapy, but in many cases (up to 50%) it does not reach normal levels. The last finding suggests that lymphocyte activation may still be present even though the disease is considered inactive under clinical criteria and support the need of prolonged immunosuppression after the first signs of remission. In AIH the serum levels of sIL-2R are elevated in all patients with active disease; all cases with "highly active" disease have significantly higher concentrations than patients with "mild activity". A good correlation has been demonstrated between elevated serum sIL-2R values and anti-asialoglycoprotein receptor (ASGPR) titer (the specific marker of AIH). The follow-up study showed a significant decrease of both sIL-2R levels and anti-ASGPR titer after 3-9 month immunosuppressive therapy. The findings support that sIL-2R and anti-ASGPR titer could serve as reliable humoral markers for disease-specific activity. Compared with inactive ulcerative colitis (UC) and Crohn's disease (CD), significantly higher levels of sIL-2R were present in the serum of patients with active disease, and in inactive disease than in healthy age-matched controls. Methotrexate (MTX) therapy of patients with refractory UC resulted in sIL-2R decrease at the end of therapeutic period (20 i.m. injections of once a week 25 mg), good responders showing > 50% decrease even at 5-7 weeks of treatment. Serum sIL-2R is elevated in all six patients with WG. Contrary to anti-neutrophil cytoplasmic antibodies (ANCA), sIL-2R remains elevated above cut-off for normal range, despite clinical improvement following immunosuppressive treatment. The last observation suggests that serum sIL-2R is not a good measure of the disease activity and argue for the need of longer immunosuppressive therapy just after the first days of clinical remission.

Oxidation of low density lipoprotein (LDL) is considered to play an important role in the development of atherosclerosis and increased levels of autoantibodies against oxidized LDL have been found in patients with various manifestations of atherosclerosis. Patients with vasculitis are prone to the development of atherosclerosis. Since production of radical oxygen species in these patients may result in increased production of oxidized LDL (Ox-LDL), we hypothesized that antibodies against Ox-LDL are elevated during lesion development in vasculitis. Therefore we measured anti Ox-LDL antibodies in 25 patients with ANCA-associated vasculitis and in 42 healthy controls using an ezyme-linked immunosorbent assay (ELISA) in which malondialdehyde modified LDL (MDA-LDL) was coated on microtitre plates. Anti Ox-LDL antibodies were significantly higher in patients as compared to controls (P = 0.0001). Anti Ox-LDL levels were also measured in 11 patients during active disease and in these same patients during complete remission. Anti Ox-LDL levels were significantly higher in patients during active disease than during full remission (P = 0.001). Our results suggest that patients with ANCA-associated vasculitis are more susceptible to oxidation of LDL, which may contribute to accelerated atherosclerosis development.

Wegener's granulomatosis is a multisystem disease characterized by granulomata of the respiratory tract and systemic necrotising vasculitis. There is a strong and specific association with autoantibodies directed against proteinase 3, a constituent of neutrophril azurophilic granules. Antibody titers correlate with clinical disease activity and predict relapses. The disease responds favorably to immunosuppressive therapy. The pathogenicity of antineutrophil cytoplasmic antibodies (ANCA), however, remains unproven. In vitro, the expression of proteinase-3 and other ANCA antigens on the surface of neutrophils and monocytes can be induced by priming with proinflammatory cytokines. Antineutrophil cytoplasmic antibodies are then able to activate these leukocytes, stimulating degranulation, the production of reactive oxygen species, and the secretion of further cytokines. Neutrophils activated by ANCA, and possibly ANCA alone, directly damage endothelial cells in vitro. An animal model of proteinase 3-ANCA-induced vasculitis has not been found. Antineutrophil cytoplasmic antibodies directed against another antigen, myeloperoxidase, are not sufficient to cause vasculitis but they promote damage in certain animal models. Thus, a considerable amount of evidence supports the notion that Wegener's granulomatosis is an autoimmune disease.

Objective: To investigate the pathogenic role of cytokines in the development of experimental autoimmune vasculitis., Methods: BALB/c mice were immunized with human IgG-ANCA from a patient with WG. Control mice were immunized with normal human IgG. Levels of mouse IgG-ANCA and other autoantibodies were determined. The mice lungs and kidneys were examined for the development of vasculitis. Levels of interleukin-1 beta (IL-1 beta), IL-2, IL-4, IL-6, interferon gamma (IFN gamma) and TNF alpha were determined by ELISA two weeks after immunization of the mice., Results: Mice immunized with human IgG-ANCA developed anti-human IgG-ANCA (= Ab2) and anti-anti-human IgG-ANCA (mouse IgG-ANCA = Ab3), while the controls did not develop these antibodies. The mice that were immunized with human IgG-ANCA developed perivascular mononuclear cell infiltrates in the lungs, suggesting vasculitis. Levels of IL-4, IL-6 and TNF alpha but not IL-1 beta, IL-2 and IFN gamma were significantly elevated in the mice 2 weeks after immunization with IgG-ANCA., Conclusion: Our results suggest a pathogenic role for IL-4, IL-6 and TNF alpha in the initiation phase of autoimmune vasculitis. This suggests that a Th2 type immune response is responsible for the initiation of experimental autoimmune lung vasculitis, similar to Wegener's granulomatosis in humans.

ANCA, implicated as having a pathogenic role in systemic vasculitis, can activate tumour necrosis factor-alpha (TNF-alpha)-primed neutrophils by cross-linking surface-expressed ANCA antigens with neutrophil FcgammaRIIa receptors to release reactive oxygen species. The FcgammaRIIa receptor exists as polymorphic variants, R131 and H131, which differ in their ability to ligate human IgG2 and IgG3. Neutrophils homozygous for the FcgammaRIIa-H131 allotype bind more efficiently to IgG3 than the FcgammaRIIa-R131 allotype and are the only human FcgammaR which bind IgG2. Our aim was to determine whether the homozygous FcgammaRIIa-H131 individuals are more susceptible to developing ANCA-associated systemic vasculitis and nephritis due to differential IgG binding and activation. FcgammaRIIa allotype was determined by both allele-specific polymerase chain reaction (PCR) and Southern blotting with allele-specific oligonucleotide probes end-labelled with 32P-gammaATP, after PCR amplification of genomic FcgammaRIIa DNA in 107 Caucasian patients with ANCA+ vasculitis (of whom 89 had renal disease) and 100 ethnically matched controls. Phenotyping of neutrophil FcgammaRIIa alleles was confirmed in some patients by quantitative flow cytometry using murine MoAbs 41H16 and IV.3. Of the patients with ANCA+ systemic vasculitis, 75 had ANCA with specificity for proteinase 3 and 32 with specificity for myeloperoxidase. Overall, no skewing in FcgammaRIIa allotypes was seen in patients compared with controls. No significant increase of the FcgammaRIIa-H131 allotype was found amongst patients irrespective of ANCA specificity, and no association between the FcgammaRIIa allotype and nephritis was found. Our data suggest that the FcgammaRIIa receptor allotype is not a major factor predisposing to the development of ANCA+ systemic vasculitis, or to nephritis.

T lymphocytes are implicated in the pathogenesis of systemic vasculitis such as Wegener's granulomatosis (WG) and polyarteritis nodosa (PAN). In the present study, we have characterized in detail the T-cell receptor (TCR) of peripheral blood T cells from eight vasculitis patients of known HLA class II genotypes. We used flow cytometry to outline the exact TCR V gene expression, complementarity determining region 3 (CDR3) fragment analysis to estimate the degree of clonality and cDNA sequencing to define the exact TCR or beta chain sequences. The TCR CDR3 region interacts with antigenic peptides presented by HLA molecules, and it is normally immensely diverse. It was therefore of particular interest to identify a common dominating TCR BV8-F/L-G-G-A/Q-G-J2S3 beta chain sequence in the CD4(+) T cells of four unrelated vasculitis patients. Furthermore, this BV8-associated CDR3 motif was linked to the HLA-DRB1*0401 allele, as well as to active disease and/or an established BV8(+) CD4(+) T-cell expansion. In contrast, age- and HLA-matched patients with rheumatoid arthritis did not harbor the described BV8 motif. These results strongly suggest that BV8(+) CD4(+) T cells with the described CDR3 motif recognize a specific antigen presented by DR4 molecules, indicating the existence of a common vasculitis-associated antigen.

Two groups of receptors for immunoglobulin G (FcgammaR) can be distinguished. Endothelial cells and placental syncytiotrophoblasts express an MHC class I-like FcgammaR important for regulation of IgG half-life and IgG transport, respectively. FcgammaR expressed on leukocytes constitute a heterogeneous family of membrane bound and soluble proteins. The various FcgammaR (sub) classes of this family differ in ligand affinity and specificity, which is determined by primary structure, glycosylation, association with signaling subunits, and environmental factors (such as serine proteases). The finding that polymorphisms of FcgammaRIIa, FcgammaRIIIa, and FcgammaRIIIb critically affect interaction with antibodies has prompted analysis in patients which provided tantalizing evidence for the relevance of FcgammaR polymorphisms as risk factors for a number of infectious and autoimmune diseases.

We treated a patient with an atypical presentation of Wegener's granulomatosis (WG) with dural involvement as the initial clinical manifestation. A 37-year-old man had a dural lesion without lower respiratory tract or renal manifestations in the initial clinical course. His only initial symptom was headache, and at disease onset computed tomography (CT) and magnetic resonance imaging (MRI) of the head revealed bilateral abnormal subdural masses. The diagnosis of WG was made based on the results of needle biopsy of the nasal polyps and the finding of positive circulating antineutrophil cytoplasmic antibodies (c-ANCA). He achieved remission on daily prednisone and cyclophosphamide with the later addition of sulfamethoxazole-trimethoprim.

Systemic vasculitides are potentially life-threatening diseases. Early and appropriate diagnosis based on case history, clinico-pathological features, and laboratory parameters, such as the presence of anti-neutrophil cytoplasmic antibodies (ANCA), is crucial for starting appropriate and, often, life-saving therapeutic measures. We report a 50-year-old female patient who presented with fever, arthralgias and hemoptysis. Skin signs included disseminated hemorrhagic pustules, ulcerations of oral and genital mucosa, subcutaneous nodules on arms and legs, and a pyoderma gangrenosum-like lesion on the right leg. Laboratory investigations revealed a peripheral eosinophilia and a positive cANCA titer. Histopathologic analysis of various biopsy specimens showed a granulomatous vasculitis in the subcutis, a nongranulomatous vasculitis with massive eosinophil infiltration in the lungs, and a segmental, necrotizing glomerulonephritis in the kidneys. Differential diagnosis included Wegener's granulomatosis, microscopic polyangiitis (MPA) and Churg-Strauss syndrome. MPA was diagnosed based on clinical and histopathological criteria. An interesting feature of this case was marked peripheral and tissue eosinophilia. Therapy consisted of cyclophosphamide and methylprednisolone. The patient went into a long-lasting clinical remission one month after starting therapy.

Objective: To investigate the prevalence and characteristics of anti-endothelial cell antibodies (AECA) in a large cohort of patients with several well defined systemic autoimmune diseases, in order to determine their relationship with the clinical and laboratory features of these diseases., Methods: Clinical and laboratory features of 216 consecutive Caucasian patients were prospectively studied. One hundred and seven patients had been diagnosed as having a primary systemic vasculitis-specifically, 39 had temporal arteritis (TA), 25 polyarteritis nodosa (PAN), 9 Wegener's granulomatosis (WG), and 34 Behcet's disease (BD)-, 90 patients had systemic lupus erythematosus (SLE), and 19 had a primary Sjogren's syndrome (SS). The AECA were determined by ELISA., Results: One hundred and four (48%) patients with systemic autoimmune diseases were found to have a positive titre of AECA. Specifically, AECA were detected in 41 (38%) patients with a primary systemic vasculitis (13 (33%) with TA, 14 (56%) with PAN, 5 (56%) with WG and 9 (26%) with BD), in 58 (63%) patients with SLE, and in 5 (26%) patients with a primary SS. In patients with a primary systemic vasculitis, those with AECA were found to have an increased prevalence of disease activity (P < 0.05). In SLE patients, those with AECA were found to have an increased prevalence of vascular lesions (P < 0.05), lupus nephropathy (P < 0.05), and anticardiolipin antibodies (aCL) (P < 0.001)., Conclusions: Patients with systemic autoimmune diseases have a high prevalence of AECA and they are associated with the presence of vascular lesions, nephropathy, and aCL in SLE, as well as with disease activity in several primary systemic vasculitis (TA, PAN, WG and BD).

Proteinase 3 is the major target antigen of antineutrophil cytoplasmic autoantibodies (ANCA) in Wegener's granulomatosis and is contained in the azurophilic granules of polymorphonuclear neutrophils, the dominant cell type in vascular lesions during the early stages of systemic vasculitis. This study questioned whether neutrophil lysosomal enzymes, once released at the site of inflammation, are able to potentiate the influx of additional neutrophils by enhancing the production of the chemotactic cytokine interleukin-8 (IL-8) by endothelial cells. Therefore, human umbilical vein endothelial cells in culture were incubated with varying concentrations of highly purified proteinase 3, human neutrophil elastase, and cathepsin G for different time periods. The supernatants were subsequently assessed for IL-8 antigen by using a sandwich ELISA. The presence of both proteinase 3 and elastase resulted in an increased production of IL-8, up to 15.6- and 4.2-fold, respectively, in a dose- and time-dependent fashion. Cathepsin G did not influence IL-8 production. Although the addition of an alpha 1-proteinase inhibitor completely abrogated elastase-mediated IL-8 production, it did not significantly influence the effect of proteinase 3. Both proteinase 3-and elastase-mediated production of IL-8 was inhibited by cycloheximide, indicating de novo synthesis. This was supported by the finding of increased IL-8 mRNA levels in proteinase 3-treated human umbilical vein endothelial cells by using Northern blot analysis. Taken together, the neutrophil lysosomal enzymes proteinase 3 and human neutrophil elastase may contribute to a self-perpetuating process of neutrophil recruitment in acute inflammation by increasing de novo synthesis of IL-8 by endothelial cells. The studies presented here also show that proteinase 3 mediates its effect independently of its enzymatic activity, indicating a hitherto unknown mode of action on endothelial cells.

A new theory to explain the pathogenesis of autoimmune diseases is proposed. It is based on the idiotypic network and does not replace other existing theories of autoimmunity. It sets out to explain the emergence of some autoimmune conditions in which the proposed autoantigen is non-immunogenic or is not identified at all. The theory is based on a series of experiments in which several experimental autoimmune diseases were induced in naive mice following active immunization with pathogenic idiotypes of autoantibodies. Following immunization with Ab1 (Id) and production of Ab2 (anti-Id), the mice developed Ab3 (anti-anti-Id) having the original autoantibody characteristics and were associated with the respective serological and clinical manifestations of the disease. The human counterpart entails infection with common pathogen. Among the anti-pathogen antibodies generated, some carry idiotypes of autoantibodies. In healthy subjects with no risk factors for autoimmunity (e.g. complement or IgA def, males, normal Ts) the idiotypic cascade ends with Ab2 (anti-Id). In subjects prone to autoimmune, Ab3 (e.g. autoantibodies) develop and may be associated with respective clinical manifestations.

Antineutrophil cytoplasmic autoantibodies (ANCA) have been described in sera of patients with several forms of systemic vasculitis, including Wegener's granulomatosis and microscopic polyarteritis. The two main targets of ANCA in vasculitis are proteinase 3 (PR3) and myeloperoxidase (MPO). ANCA are capable of activating neutrophils primed by tumor necrosis factor-alpha (TNF-alpha) in vitro, which may be relevant for the induction of the vascular inflammation observed in vivo. Recently, it has been suggested that engagement of Fc gamma receptor IIa (Fc gamma RIIa) on the neutrophils is involved in the activation by ANCA. In the present study, we show that activation of the neutrophil respiratory burst by anti-PR3 and anti-MPO is strongly enhanced after TNF priming and lost on removal of the Fc parts of the antibodies. Similar results were obtained when the neutrophils were activated with antibodies against known membrane antigens without major changes in the expression of the target antigens. The TNF-induced enhancement of the neutrophil activation was not observed when adherence of the cells was prevented by continuous stirring of the suspension or by the addition of CD18 antibodies before TNF exposure. Hence, our results indicate that engagement of both Fc gamma RIIa and beta 2 integrins is instrumental in neutrophil activation induced by ANCA.

Autoimmune diseases may be classified into two groups: autoantibody-mediated and cellular-mediated. In many autoimmune conditions the autoantigen is well-defined, immunogenic and, upon immunization of the naive animal, will lead to the production of autoantibodies and, eventually, to the induction of the respective autoimmune disease. However, in certain autoimmune diseases the autoantigen is either ill-defined, or is not immunogenic, or is intracellular. In many of these situations it is difficult to explain the emerging clinical findings by the mere binding of the autoantibody to the autoantigen. We herewith propose an additional mechanism for autoimmune disease induction, employing active idiotypic immunization. The induction of the disease is exemplified by three clinical models-SLE, APS, and Wegener's granulomatosis. The implications for human disease are discussed.