Granulomatous Manifestations Research Articles

ANCA-associated vasculitis in children.

Childhood-onset anti-neutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAVs) are a group of systemic autoimmune disorders characterized by inflammatory cells infiltration, necrosis of small-medium blood vessels and autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). Primary AAVs in children are rare with a higher female preponderance, a peak age at onset in the second decade and median age at diagnosis 12–14 years [1]. They are classified into [2] granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA) and renal-limited AAVs (Fig. 1). GPA, the estimated incidence of which in Europe is less than 1 per 2 million population/year, is more common than MPA and EGPA but recently literature demonstrated that MPA was more frequent than GPA in children [3]. ... AAVs may be primary or secondary. Several factors may have a role: ... Patients present general symptoms such as weight loss, poor feeding and fever preceding systemic manifestations. Localized forms affecting single organs may lead to delayed diagnoses. There is an overlap in clinical features of GPA and MPA since both may present a high incidence of gastrointestinal manifestations (chronic nausea, diarrhea, abdominal pain), muco-cutaneous manifestations (oral and genital ulcers, palpable purpura, petechial rash, livedo, subcutaneous nodules) and musculoskeletal manifestations (arthralgia, myalgia, arthritis). MPA can be distinguished from GPA clinically by the lack of granulomatous manifestations and serologically by its more frequent association with MPO-ANCA. Both EGPA and GPA are characterized by granulomatous inflammation and necrotizing vasculitis involving small- and medium-sized vessels, but EGPA is distinguished from GPA by eosinophilia and asthma.

Pulmonary sarcoid-like granulomatosis during etanercept treatment for inflammatory arthritis: A case series and literature review

Rationale: Tumor necrosis factor-alpha (TNF-α) inhibitors have been implicated in the development of sarcoid-like granulomatous inflammation when used for treatment of a variety of immune-related diseases. The mechanisms are not completely understood, and the clinical, radiographic and histologic findings of this condition require further description. The literature surrounding this is largely limited to single case reports. Objectives: The objective of this study was to describe pulmonary sarcoid-like granulomatosis in 5 patients receiving etanercept therapy prescribed for inflammatory arthritis. Methods: We retrospectively reviewed the medical records of 5 patients who developed granulomatous sarcoid-like manifestations while on treatment with etanercept for inflammatory arthritis. Data surrounding clinical features and radiographic and histologic findings, as well as clinical outcomes, were described. Results: Median time from initiation of treatment to development of symptoms was 36 months (range 7-60 months). All patients had radiographic abnormalities on chest imaging, with 4 patients having adenopathy on thoracic imaging, and 2 of the 5 patients having parenchymal involvement. Biopsy evidence of granulomatous inflammation was seen in all patients. Three of 5 patients had discontinuation of etanercept when the diagnosis was made, and all experienced improvement. Of the 2 patients that were continued on etanercept, 1 had spontaneous improvement and the other had stable, asymptomatic radiographic abnormalities. Only 1 patient was treated with corticosteroids. Conclusion: Pulmonary sarcoid-like granulomatosis is incompletely understood and establishing the causal role of these drugs in sarcoid-like lung disease is difficult. We hope that the addition of these 5 cases of etanercept-related pulmonary sarcoid-like granulomatosis will add to our future understanding of this response to etanercept and other anti-TNF-α agents.

Rituximab plus methotrexate combination as a salvage therapy in persistently active granulomatosis with polyangiitis.

The aim of this study was to describe the efficacy and safety of rituximab and MTX (RTX/MTX) combination therapy in ANCA-associated vasculitides (AAV). A retrospective French nationwide study was conducted in patients with AAV who received RTX/MTX combination therapy for persistently active disease. Seventeen patients were included. All patients had granulomatosis with polyangiitis (GPA), with positive ANCA in 76% of them, mainly with PR3-ANCA specificity. Sixteen patients (94%) had priorly failed to achieve remission with RTX and 11 (65%) with CYC. Patients had experienced a median of 3 (2-4) flares. Manifestations requiring RTX/MTX combination therapy were subglottic or bronchial stenosis in 6 patients (35%), orbital mass in 6 (35%), disabling ENT involvement in 2 (12%), and epiduritis and pachymeningitis in 1 case (6%) each. The median follow-up duration for the RTX/MTX combination therapy was 11 months (11-26 months). At 6 months, global response had been achieved in 15 patients (88%), including partial response in 11 (65%) and complete response in 4 (24%). At last evaluation, global response had been achieved in 16 patients (94%). Seven patients (41%) experienced severe adverse events (grade 3 or 4), including infections in 4 (24%) and hepatitis in 2 (12%). Combination therapy was withdrawn in 4 patients (24%), but never for safety concerns. In contrast, the MTX dose was decreased in 2 patients (12%) because of adverse events. One patient died of an unknown cause. RTX/MTX combination therapy could be an effective salvage therapy to treat persistently active GPA with granulomatous manifestations, with an acceptable safety profile.

Les déficits immunitaires communs variables (DICV) : partie 1 : évolution des critères diagnostiques et des connaissances génétiques

Common variable immunodeficiency disorders (CVID) are a heterogeneous group of conditions with hypogammaglobulinemia as the common denominator. These are the most common symptomatic primary immunodeficiency disorder in adults. Two different clinical forms are described: one group only develops infections, while a second includes (sometimes without infections, at least at the onset of disease course) a variety of non-infectious autoimmune, inflammatory, granulomatous and/or lymphoproliferative manifestations, sometimes revealing the disease and often observed in Internal Medicine. The international diagnostic criteria for CVID were updated in 2016 and are the subject of several comments in this general review. The recent use of new sequencing techniques makes it possible to better genetically define CVID. The identification of such a genetic disease makes it possible to treat pathophysiologically, in particular autoimmune and lymphoproliferative complications, with targeted treatments, sometimes used in other diseases. Determining a genetic disease in these patients also makes it possible to provide appropriate genetic counseling, and therefore to monitor mutated individuals, symptomatic or not.

Les déficits immunitaires communs variables (DICV) : partie 2. Mise à jour clinique et thérapeutique

Common variable immunodeficiency disorders (CVID) are the most common symptomatic primary antibody deficiency in adults with an estimated prevalence of 1/25,000. The most frequent clinical manifestations are upper respiratory tract infections (including pneumonia, bronchitis, and sinusitis) predominantly with Streptococcus pneumoniae or H. influenzae. However, CVID are complicated in 20 to 30 % of cases of non-infectious manifestations which have been well characterized in recent years. Several complications can be observed including autoimmune, lymphoproliferative, granulomatous or cancerous manifestations involving one or more organs. These complications, mostly antibody-mediated cytopenias, are correlated with a decrease in the number of circulating switched memory B cells. Replacement therapy with polyvalent gammaglobulins has greatly improved the prognosis of these patients but it remains poor in the presence of digestive complications (especially in the case of chronic enteropathy and/or porto-sinusoidal vascular disease), pulmonary complications (bronchiectasis and/or granulomatous lymphocytic interstitial lung disease) and when progression to lymphoma. Much progress is still to be made, in particular on the therapeutic management of non-infectious complications which should benefit in the future from targeted treatments based on knowledge of genetics and immunology.

Granulomatous inflammation in the manifestation of chronic granulomatous disease: a clinical case report

Chronic granulomatous disease is a primary immunodeficiency, characterized by a violation of the oxygen-dependent mechanisms of phagocytosis. Mutations in the genes encoding proteins of the NADPH-oxidase complex lead to a violation of the respiratory burst. Clinical manifestations are recurrent bacterial and fungal infections, and the development of granulomatous complications due to a defect in autophagy, accompanied by an increase in the level of interleukin-1 inthe blood. The treatment of this disease is continuous preventive antimicrobial therapy, and specific therapy for the treatment of granulomatous complications. Hematopoietic stem cell transplantation from an allogeneic or unrelated donor is currently considered to be only radical treatment for CGD. This article presents a clinical case of the manifestation of an X-linked form of chronic granulomatous disease with granulomatous manifestations in the absence of an infectious history. Parents patient agreed to use personal data in research and publications.

Inherited p40phox Deficiency Differs From Classic Chronic Granulomatous Disease

To characterize clinical and laboratory aspects of p40phox deficiency, a unique autosomal recessive form of chronic granulomatous disease (CGD) previously described in only 1 patient.The population included 24 patients with p40phox deficiency from 12 families in 8 countries. Both male and female patients are reported, with age ranging from 1 to 47 years.Clinical history of each case was collected, including autoinflammatory manifestations and infection history. Laboratory analysis included both gene sequencing and numerous functional studies of the immune system.Mean age at diagnosis for symptomatic patients was 15 years (range: 1–46 years). Twenty patients were symptomatic. Four were asymptomatic (age 1–10 years, recognized by family history). Of the symptomatic patients, skin inflammation was present in 50%, and granulomatous gastrointestinal manifestations were present in 50%, with varied presentation from oral ulcers to severe Crohn-like inflammatory bowel disease. Cutaneous infections were reported in 42%. The phorbol myristate acetate–induced dihydrorhodamine (DHR) oxidation test gave normal or just below normal results for all patients.Excessive inflammatory lesions of the skin (lupuslike) and gastrointestinal tract (Crohn-like) are common in patients with p40phox deficiency. Compared with classic CGD, it is often diagnosed later in life and demonstrates a normal DHR laboratory test result (the laboratory test widely used for diagnosis of CGD). Patients experience peripheral bacterial infections, but fungal infections and invasive infections of any type are not common. Identification of 4 asymptomatic children demonstrates that there is incomplete clinical penetrance, at least until adolescence.It is essential for pediatricians to be aware of this disease and how it differs from classic CGD. Patients may be under their care who have been managed by other subspecialists (dermatology, rheumatology, gastroenterology) but have never been recognized to have an underlying p40phox deficiency. Additionally, immunologists are only recently learning that this form of CGD is not detectable by routine DHR. Therefore, if a patient has clinical signs and symptoms that fit the diagnosis, immunology consultation is warranted even if the immune system has been evaluated in the past. Genetic testing should be considered to confirm the diagnosis.

A Misleading Diagnosis of Sarcoidosis in an Older Woman.

Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency and has a reported prevalence of approximately 1:25,000 to 1:50,000. The fact that it is rarely considered as a diagnosis in adults can lead to diagnostic delay, especially in older patients, and to complications such as bronchiectasis and excess mortality. However, practitioners should first exclude common causes of hypogammaglobulinaemia before considering CVID. Here we present a case of CVID revealed by prolonged fever and complicated with granulomatous manifestations and bronchiectasis in an older woman without a history of recurrent infections.LEARNING POINTSCommon variable immunodeficiency (CVID) should be considered in atypical cases with unexplained chronic signs such as fever of unknown origin (even in older patients) after tuberculosis, HIV, neoplasia and connective tissue disease have been ruled out.Common causes of hypogammaglobulinaemia should be excluded before CVID is considered.CVID can mimic sarcoidosis.

Granulomatosis with polyangiitis according to geographic origin and ethnicity: clinical-biological presentation and outcome in a French population.

Granulomatosis with polyangiitis (GPA) mainly affects white Europeans, but rarely GPA may also affect non-Europeans. This study aimed to describe GPA clinical-biological presentation and outcome in black sub-Saharan Africans and Afro-Caribbeans and in North Africans. Among 914 GPA patients included in the French Vasculitis Study Group database, geographic origin and ethnicity were known for 760. Clinical-biological presentations and outcomes of white Europeans vs black sub-Saharans and Afro-Caribbeans and vs North Africans were analysed. Among the 760 patients, 689 (91%) were white Europeans, 33 (4.3%) were North Africans and 22 (2.9%) were sub-Saharans (n = 8) or Afro-Caribbeans (French West Indies, n = 14). Black sub-Saharans and Afro-Caribbeans, compared with white Europeans, were significantly younger at GPA diagnosis (P = 0.003), had more frequent central nervous system involvement (P = 0.02), subglottic stenosis (P = 0.002) and pachymeningitis (P = 0.009), and tended to have more frequent chondritis and retroorbital tumour. Median serum creatinine levels and Birmingham Vasculitis Activity Score were significantly lower in sub-Saharans and Afro-Caribbeans (P = 0.002 and P = 0.003, respectively). In contrast, in comparison with white Europeans, North Africans had only less frequent arthralgias (P = 0.004). Time to relapse was shorter for black sub-Saharans and Afro-Caribbeans compared with white Europeans [adjusted HR = 1.96 (95% CI: 1.09, 3.51) (P = 0.02)], and did not differ for North Africans. In contrast, overall survival was not significantly different according to ethnicity. Our findings indicated different GPA clinical presentations in white Europeans and sub-Saharans and Afro-Caribbeans, with black patients having more frequent severe granulomatous manifestations. In addition, time to relapse was significantly shorter for black sub-Saharans and Afro-Caribbeans compared with white Europeans.

Clinical pathology of granulomatous inflammation : With special emphasis on the lungs and central nervous system

Granulomatous diseases are not rare in routine daily diagnostics. Granulomas are an indication of a sufficiently functioning immune system. In the absence of granulomas, apossible immunodeficiency should also be considered (e.g. in tuberculosis) in the diagnostic procedure. Many types of diseases with different etiologies can cause granulomatous manifestations. Diagnostic procedures should be oriented to the clinical symptoms and should include blood analyses, radiography, especially computed tomography (CT) and magnetic resonance imaging (MRI) and sampling for histology or cytology. In the case of proven granulomatous inflammation an infectious etiology should first be excluded. The diagnosis of agranulomatous disease should always be confirmed by histopathology when possible. In this study the origins and general histopathological classification of granulomatous diseases are presented. In addition to the most common granulomatous diseases, some special and rare forms are discussed, which should also be considered in the differential diagnostic process. The diagnosis of agranulomatous disease should always be made in an interdisciplinary cooperation and requires close collaboration between radiologists, internists, pathologists and specialists in laboratory parameters.

Managing Inflammatory Manifestations in Patients with Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by lack of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which results in inflammatory dysregulation and increased susceptibility to infections. Patients with CGD may develop severe obstructive disorders of the digestive tract as a result of their dysregulated inflammatory response. Despite a growing focus on inflammatory manifestations in CGD, the literature data on obstructive complications are far less extensive than those on infectious complications. Diagnosis and management of patients with concomitant predispositions to infections and hyperinflammation are particularly challenging. Although the inflammatory and granulomatous manifestations of CGD usually respond rapidly to steroid treatment, second-line therapies (immunosuppressants and biologics) may be required in refractory cases. Indeed, immunosuppressants (such as anti-tumor necrosis factor agents, thalidomide, and anakinra) have shown some efficacy, but the value of this approach is controversial, given the questionable risk-to-benefit ratio and the small numbers of patients treated to date. Significant progress in allogeneic hematopoietic stem cell transplantation (the only curative treatment for CGD) has been made through better supportive care and implementation of improved, reduced-intensity conditioning regimens. Gene therapy may eventually be an option for patients lacking a suitable donor; clinical trials with new, safer vectors are ongoing at a few centers.

Moderator's view: Should all patients with ANCA-associated vasculitis be primarily treated with rituximab?

Experience with rituximab in patients with new ANCA-associated vasculitis (AAV) is still very limited, especially in patients with severe (organ- or life-threatening) AAV. Rituximab may be more effective in anti-PR3 AAV, but potentially less effective in some granulomatous manifestations of AAV. We do not know what the response is to rituximab on the tissue level. Rituximab induction needs to be followed by maintenance treatment, and potentially very long rituximab maintenance may result in higher risk of rituximab-related complications (e.g. decrease in IgG levels). Long-term experience with rituximab in AAV is insufficient. Treatment with rituximab is more expensive than the standard treatment with cyclophosphamide and corticosteroids and seems to be cost-effective only in patients primarily treated with cyclophosphamide. Rituximab can be used in some newly diagnosed patients with AAV (e.g. women with child-bearing potential, or patients with active vasculitis and severe infection), but with the available information, it may be too early to use it as a first-line treatment in all new AAV patients.

Impact of rituximab trials on the treatment of ANCA-associated vasculitis

ANCA-associated vasculitis (AAV) is a subgrouping of autoimmune disorders characterized by a chronic relapsing course. Induction therapy is usually effective, but 70% of patients will relapse and 20% develop refractory disease. In the relapsing and refractory subgroups, treatment is complicated by the cumulative exposure to toxic drugs that contribute to poor long-term outcomes. The anti-CD20 monoclonal antibody rituximab (RTX) depletes B cells, and the success of this targeted therapy has contributed to the evidence supporting a central role for B cells in AAV pathogenesis. Initial proof of RTX effectiveness originated from small, prospective trials and retrospective surveys conducted in AAV patients with relapsing and refractory disease; high remission rates permitted the reduction of glucocorticoids (GCS) doses and withdrawal of immunosuppressives. There has been controversy over the effectiveness of RTX in patients with predominantly granulomatous manifestations, where response rates have varied between studies, in part due to different RTX dosing regimens. These studies were followed by comparison of RTX against cyclophosphamide (CYC) for remission induction of new or relapsing AAV in two randomized trials, which led to the licensing of RTX for this indication. Subsequent attention has been turned to the use of RTX as a relapse prevention agent, to the potential for GCS sparing and to RTX-associated toxicity. We will discuss the impact that the results of RTX clinical trials have had on the management of AAV patients.

Granuloma in ANCA-Associated Vasculitides: Another Reason to Distinguish Between Syndromes?

The 2012 renewed Chapel Hill Consensus Conference (CHCC) officially named three clinicopathological entities, i.e. granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA), as major variants of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). Recent genetic and cohort studies revealed the need for further differentiation between the entities, for example regarding differences in outcome. As well as ANCA reactivity, upper and lower airway disease were found to be differentiating factors for AAV variants, improving prognostic ability regarding relapse prediction and associated clinical features. Extravascular granulomatosis, or "granuloma", which describes both clinically relevant granulomatous manifestations and histopathologically documented granulomatous inflammation, is characteristic of localized and systemic GPA, but not MPA. This review summarizes new knowledge regarding granuloma in the head and neck region of AAV, its histomorphological equivalents in the upper and lower respiratory tract, and evidence for a granulomatous phenotype of a persistent localized GPA variant. This comprises the development of disease activity and damage scores for extravascular lesions in the ear, nose, and throat (ENT) regions, and imaging techniques. In addition, findings linking extravascular manifestations to granulomatous inflammation are described. We hypothesize that, as for ANCA, necrotizing granulomatous inflammation and its clinical manifestations are discriminators, assisting subclassification of AAV and/or GPA subphenotypes which will be useful both for designing clinical trials and for treating patients successfully.

OP0184 Retrospective monocentric cohort of orbital masses in granulomatosis with polyangiitis (GPA, wegener’s): rare disease manifestation with a refractory disease course

BackgroundFew studies with small patients numbers (n=15) [1, 2] have addressed the disease course of orbital masses in GPA. These studies suggest an aggressive course of orbital masses in spite...

FRI0341 Urinary hmgb1 levels are associated with cd4+ t-cells in urine in patients with anca-associated vasculitis and active nephritis.

BackgroundHigh mobility group box 1 (HMGB1) is a nuclear non-histone protein that acts as an alarmin when released in the extra-cellular medium by necrotic or activated cells. High serum HMGB1...

FRI0217 HMGB1 in ANCA-associated vasculitis: A longitudinal study

BackgroundHigh mobility group box 1 (HMGB1) is a non-histone DNA binding protein that is passively released by dying cells or actively secreted by immunologic competent cells. Higher levels of HMGB1...

Urinary HMGB1 levels are associated with CD4+ T-cells in urine in patients with ANCA-associated vasculitis and active nephritis

Background High mobility group box 1 (HMGB1) is a nuclear non-histone protein that acts as an alarmin when released in the extra-cellular medium by necrotic or activated cells. High serum HMGB1 levels have been found in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and active nephritis as well as in patients with granulomatosis with polyangiitis (GPA) and predominant granulomatous manifestations. High serum and urinary HMGB1 levels have also been found in patients with systemic lupus erythematosus (SLE) and active nephritis. Objectives To evaluate serum and urinary levels of HMGB1, CD4+ T-cells and effector memory T-cells (CD4+ T EM )in peripheral blood (PB) and urine from patients with AAV and active nephritis. Methods 24 AAV patients with active nephritis and 10 healthy controls (HC) were evaluated in a cross-sectional study. Clinical diagnosis of GPA or microscopic polyangiitis (MPA) was made according to the European Medicines Agency algorithm whereas patients with isolated renal involvement, ANCA positivity and/or biopsy-proven pauci immune necrotizing glomerulonephritis were classified as renal limited vasculitis (RLV). Serum and urinary levels of HMGB1 were measured by Western blot while CD4+ T-cells and CD4+ T EM cells (CD4+CD45+RO+CCR7-) in urine were analyzed by flow cytometry. Disease activity was evaluated according to the Birmingham Vasculitis Activity Score (BVAS). Results Median urinary intensity of HMGB1 was significantly higher in AAV patients when compared to HC [5.15 (IQR 3.52-9.25) vs. 2.58 (1.88-4.24); P =0.006] whereas no difference was found among different AAV subsets regarding median urinary intensity of HMGB1 [GPA: 4.1 (2.6-16.4) vs. MPA: 5.1 (4.4-5.6) vs. RLV 5.7 (1.4-13.6); P =0.951] and HMGB1/creatinine ratio [GPA: 0.93 (0.29-3.91) vs. MPA: 1.29 (0.90-1.89) vs. RLV 0.54 (0.14-1.28); P =0.186]. In urine of AAV patients, median CD4+ T-cells was 125.00 (58.93-429.28) cells/ml and CD4+ T EM cells was 93.24 (43.21-343.37) cells/ml. Urine levels of HMGB1 were positively correlated with CD4+ T-cell counts in urine (rho: 0.454; P =0.014) and with CD4+ T EM cells in urine (rho: 0.378; P =0.049) while a tendency for a negative correlation between urinary HMGB1 and CD4+ T-cells in PB (rho: -0.307; P =0.083). No correlation could be found between urine levels of HMGB1 and 24 hour proteinuria (rho: 0.065; P =0.390), creatinine clearance (rho: -0.049; P =0.832), BVAS (rho: -0.203; P =0.171) and serum HMGB1 (rho: -0.046; P =0.419). Conclusions Urine HMGB1 levels are increased in AAV patients with active nephritis when compared to HC and are associated with CD4+ T-cells in urine suggesting that urine HMGB1 is a biomarker for renal activity in AAV.

HMGB1 in ANCA-associated vasculitis: A longitudinal study

Background High mobility group box 1 (HMGB1) is a non-histone DNA binding protein that is passively released by dying cells or actively secreted by immunologic competent cells. Higher levels of HMGB1 have been found in ANCA-associated vasculitis (AAV), especially in patients with granulomatosis with polyangiitis (GPA) and active disease. HMGB1 has been associated with granulomatous manifestations of GPA and with biopsy-proven renal involvement in AAV. Objectives To measure HMGB1 levels longitudinally in a cohort of patients with AAV in order to evaluate the association with disease activity, remission, relapses, and specific organ involvement. Methods HMGB1 levels were tested by ELISA at diagnosis, at least twice during the remission period and during a disease flare. Disease activity was ascertained using the Birmingham Vasculitis Activity Score (BVAS). Results 50 patients with AAV and 35 age and sex matched healthy controls (HC) (58.5±14.1 years vs. 55.1±11.7 years at baseline; P=0.256), frequency of females (44.0% vs. 51.4%; P =0.499) were included. The frequency of each AAV subgroup was as follows: GPA (62%), microscopic polyangiitis (MPA) (20%), isolated necrotizing glomerulonephritis (iNGN) (16%) and Churg-Strauss syndrome (CSS) (2%). Localized disease was found in 16% and renal involvement in 74% at disease onset. Patients and HC had similar mean levels of HMGB1 at baseline (2.61±1.83 vs. 2.34±0.94 ng/mL; P=0.389). Patients with localized disease presented higher median levels of HMGB1 than those with generalized disease but this difference was not significant [3.14 (0.50-9.03) vs. 1.97 (0.46-7.54) ng/mL; P=0.233] whereas patients with renal involvement had lower levels of HMGB1 in comparison to those without renal involvement at baseline (2.29±1.48 vs. 3.52±2.41 ng/mL; P=0.035). Negative correlations were found between serum HMGB1 and 24 hours proteinuria levels (ρ = -0.352; P=0.038) and between HMGB1 and serum creatinine at baseline (ρ = -0.287; P=0.045). The mean follow-up period was 53.4 months and at least one relapse was observed in 34.0% of patients. Among relapsing patients, at least one relapse was found in 64.7% and 2 relapses in 35.3%. At baseline, relapsing patients presented significantly higher mean BVAS when compared to non-relapsing patients (20.2±8.8 vs. 15.3±5.8; P=0.038) while other baseline features were similar between relapsing and non-relapsing patients including age, gender, ANCA specificity, HMGB1 and C-reactive protein (CRP) levels. Median HMGB1 levels were as follows: 2.12 ng/mL at baseline, 1.44 ng/mL and 1.90 ng/mL in patients in remission 3 and 11 months after commencing therapy (P=0.029). Median HMGB1 levels were 2.26 ng/mL and 2.04 ng/mL in the first and in the second relapse, respectively. Conclusions Serum HMGB1 levels were similar between patients with AAV and controls at baseline and renal involvement may account for unexpectedly lower levels of HMGB1 in patients with AAV at baseline, possibly due to urinary loss in patients with proteinuria. No clear relation between HMGB1 levels and disease activity could be found. Nonetheless, a significant decrease in HMGB1 levels was observed in AAV patients from baseline to remission.

Update Granulomatose mit Polyangiitis (GPA, Wegener-Granulomatose)

Granulomatosis with polyangitis (GPA, Wegener's granulomatosis) is characterized by a granulomatous inflammation of the respiratory tract and a necrotizing ANCA-associated small to medium-size vessel vasculitis with a predilection for the lungs (pulmonary capillaritis) and kidneys (necrotizing glomerulonephritis). The disease evolves stage-wise and typically starts as inflammation of the respiratory tract followed by development of systemic vasculitis manifestations. Today, treatment is evidence-based and adapted according to activity and disease stage which has resulted in a significant improvement in long-term outcome. Early mortality during the first year of treatment poses one of the main problems and is a result of infections under immunosuppressive treatment. Furthermore, treatment of refractory disease activity which is often represented by granulomatous manifestations is still a challenge and may result in significant organ damage if not treated successfully.