Cornelis Kallenberg

2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides

2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides J. Jennette;R. Falk;P. Bacon;N. Basu;M. Cid;F. Ferrario;L. Flores-Suarez;W. Gross;L. Guillevin;E. Hagen;G. Hoffman;D. Jayne;C. Kallenberg;P. Lamprecht;C. Langford;R. Luqmani;A. Mahr;E. Matteson;P. Merkel;S. Ozen;C. Pusey;N. Rasmussen;A. Rees;D. Scott;U. Specks;J. Stone;K. Takahashi;R. Watts; Arthritis & Rheumatism

EULAR recommendations for the management of primary small and medium vessel vasculitis

Objectives: To develop European League Against Rheumatism (EULAR) recommendations for the management of small and medium vessel vasculitis. Methods: An expert group (consisting of 10 rheumatologists, 3 nephrologists, 2 immunologists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search using a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of small and medium vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion. Results: In all, 15 recommendations were made for the management of small and medium vessel vasculitis. The strength of recommendations was restricted by low quality of evidence and by EULAR standardised operating procedures. Conclusions: On the basis of evidence and expert consensus, recommendations have been made for the evaluation, investigation, treatment and monitoring of patients with small and medium vessel vasculitis for use in everyday clinical practice.

Association of Chronic Nasal Carriage of Staphylococcus aureus and Higher Relapse Rates in Wegener Granulomatosis

Wegener granulomatosis is a systemic disease characterized by necrotizing granulomatous inflammation of the upper and lower respiratory tract in combination with vasculitis and focal necrotizing crescentic glomerulonephritis [1]. Treatment with cyclophosphamide in combination with corticosteroids has proved highly successful, although side effects may be severe and sometimes lethal [2]. After remission is achieved, the course of the disease is highly variable and unpredictable. Most patients have relapses at variable intervals requiring re-institution of immunosuppressive therapy. Serial titration of antineutrophil cytoplasmic antibodies (ANCA) is helpful in predicting the occurrence of relapses [3-6]. The pathogenesis of the disease is not well known. Several anecdotal reports have noted beneficial results of sulfamethoxazole-trimethoprim in the treatment of refractory Wegener granulomatosis or limited Wegener granulomatosis localized to the respiratory tract [7-10]. These findings have raised speculation regarding a possible role for infectious agents in the induction of disease activity in Wegener granulomatosis. Recently, it was noted that patients with Wegener granulomatosis frequently have symptoms of a respiratory tract infection at the time of ANCA titer elevation [4]. Previous studies also found that many patients had respiratory tract infections either at the onset of the disease or before a relapse [11, 12]. Virtually every patient with Wegener granulomatosis has secondary infections of the paranasal tissues, predominantly with Staphylococcus aureus, and infections invariably respond to antistaphylococcal antibiotics [2]. Nasal carriage of S. aureus is considered a risk factor for S. aureus infections [13-16]. No prospective studies have been done on the frequency of these infections or the relation of nasal carriage rate of S. aureus to disease activity or levels of ANCA in patients with Wegener granulomatosis. We examined several possible risk factors for relapse of Wegener granulomatosis. Methods All consecutive patients with biopsy-proven Wegener granulomatosis visiting our outpatient clinic from January 1988 to July 1991 entered the study. The diagnosis of Wegener granulomatosis was based on clinical and histologic criteria [2]. At each visit, usually every 4 to 6 weeks, patients were evaluated for signs and symptoms attributable to active Wegener granulomatosis and infections; blood samples were obtained for ANCA determinations; a swab culture of the anterior nares was taken; and medication was noted, with special emphasis on current or recent use of antibiotics. Because antibiotics can influence the results of nasal cultures, results of cultures taken during or within 4 weeks after a course of antibiotics were disregarded, as were cultures taken during hospitalization because the carrier rate may be enhanced by hospital stay [13]. No attempts were made to eliminate S. aureus carriage, although proven or suspected infections were treated with appropriate courses of antistaphylococcal antibiotics. Relapses of Wegener granulomatosis were treated, and immunosuppressive agents were tapered according to a protocol described previously [3]. Briefly, patients were initially treated for active Wegener granulomatosis with cyclophosphamide, 2 mg/kg body weight daily, and prednisolone, 1 mg/kg daily. Doses of cyclophosphamide were adjusted to maintain the leukocyte count above 4.0 109/L. In the absence of signs of active disease, the daily dose of cyclophosphamide was tapered every 3 months by 25 mg. Daily prednisolone was tapered after 6 weeks by 10 mg every 2 weeks until the dose reached 30 mg and thereafter by 5 mg every 2 weeks. Given the possible beneficial influence of cotrimoxazole in Wegener granulomatosis, patients receiving prolonged continuous treatment with antibiotics, arbitrarily defined as more than 6 weeks, were excluded. To establish true stable nasal carriage of S. aureus, only patients with at least 1 year of follow-up were included in the analysis. Patients were considered to have relapsed when they satisfied one of the following criteria in which the manifestations in question had to be new or recurrent findings [4]: 1. Progressive glomerulonephritis, a decrease in renal function of 30% or more within 3 months in combination with (microscopic) hematuria or evidence of acute necrotizing lesions on renal biopsy. 2. Pulmonary infiltrates with or without cavitation with rising C-reactive protein levels in the absence of infection or signs of malignancy. 3. Sinusitis, otitis, ulceration of nasal mucosa, or proliferative mass, in combination with necrotizing granulomatous inflammation on biopsy. 4. Miscellaneous (progressive mononeuritis multiplex, cranial nerve palsy, cerebral vasculitis, necrotizing scleritis, orbital pseudotumor, progressive tracheal stenosis with active disease on biopsy, peripheral gangrene, necrotizing vasculitis of medium-sized or small muscular arteries). An upper-airway infection was considered present when patients had clinical signs involving the pharynx, trachea, nasal and paranasal tissues, and ear, in combination with a positive culture or serologic evidence, and when patients had clinical signs suggesting infection, without microbiologic evidence but with a prompt response to appropriate antibiotic treatment. Viral serologic tests were done only when clinically indicated, as were serologic tests for Mycoplasma, Chlamydia, and Legionella species. Urinary tract infections were defined by leukocyturia in combination with bacterial concentrations of 105 colony-forming units per mL or greater. Patients were considered to be chronic nasal carriers when 75% or more of their nasal cultures grew S. aureus [14] and nonchronic carriers when less than 75% (or no) nasal cultures grew S. aureus. Patients were also grouped according to their ANCA status during the study. Patients were considered persistently positive for ANCA when all ANCA measurements were positive during the study and intermittently positive when periods with positive ANCA test results were interrupted by at least two consecutive negative readings. Patients were considered persistently negative for ANCA when all consecutive ANCA measurements were negative from 6 months after the previous period with disease activity [6]. Destructive nasal lesions were defined as visible perforations of the nasal septum or saddle-nose deformity. Nasal cultures were taken by firmly rotating a sterile cotton-tipped swab (Transwab; Amies Med Elpo, Italy) in each anterior naris. The swabs were inoculated on 5% sheep-blood agar and salt mannitol agar (Oxoid; Basingstoke, England) for 48 hours at 35 C. Isolates were identified as S. aureus by the typical appearance of the colonies that were coagulase positive by slide coagulase testing and the ability to cleave DNA. Antineutrophil cytoplasmic antibodies were measured by indirect immunofluorescence on ethanol-fixed granulocytes [17]. Antineutrophil cytoplasmic antibodies were designated as c-ANCA when the fluorescence pattern was granular with a decrease in fluorescence intensity toward the periphery of the cells and as p-ANCA when a perinuclear-to-nuclear pattern was observed. The specificity and sensitivity of c-ANCA determinations in our laboratory for active Wegener granulomatosis have been previously reported [3]. In addition, the antigenic specificity of ANCA for either proteinase-3, myeloperoxidase, and elastase was tested by ELISA as previously described [18]. Statistical Analysis Differences in frequencies of categorical variables between groups were studied by the chi-square test. The continuous variables were tested with the Wilcoxon rank-sum test. Disease-free interval curves were calculated using the Kaplan-Meier method [19]. The first relapse during the study period was counted from the most recent period of disease activity, either diagnosis or a prestudy relapse. Patients without relapse were censored at the end of the study. Differences between groups in disease-free interval were studied by the log-rank test [20]. Confounding influences were tested by tests for trend and, when statistically significant, the log-rank test was done after stratification for the confounding variable [20]. Stepwise Cox proportional-hazards regression analysis (BMDP statistical software, BMDP, Inc., Cork, Ireland) with disease-free interval as the dependent variable was used to adjust the observed effect of S. aureus carrier status for other potential prognostic factors and to determine the independent influence of these other factors on disease-free interval [21]. Other variables included age, sex, disease-free interval before the start of the study, time since diagnosis, renal function measured as creatinine clearance (used as both a continuous and a categorical variable), nasal structure, number of documented infections during the study, history of previous relapses, and the time at which the patient was diagnosed as having Wegener granulomatosis (before or during the study). The termination of immunosuppressive therapy after the previous period of disease activity was included as a time-dependent covariate. Hazard ratios are reported as relative risks with 95% CIs computed from the exponential in the regression model using only covariates whose coefficients had a P value 0.10. Association of categorical variables was assessed by chi-square analysis, and associations were expressed by relative risk and its 95% CI [22]. A two-tailed P value < 0.05 was considered statistically significant. Results Of 71 patients who entered the study, 57 were analyzed, including 33 with an established diagnosis of Wegener granulomatosis before January 1988. The excluded patients included 11 patients initially referred for diagnosis or treatment but who requested follow-up at the referral hospital, 1 patient who died from gram-negative septicemia and pneumonia 8 months after being diagnosed with Weg

EULAR Recommendations for the management of large vessel vasculitis

Objectives: To develop European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis. Methods: An expert group (10 rheumatologists, 3 nephrologists, 2 immunolgists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search through a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of large vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion. Results: Seven recommendations were made relating to the assessment, investigation and treatment of patients with large vessel vasculitis. The strength of recommendations was restricted by the low level of evidence and EULAR standardised operating procedures. Conclusions: On the basis of evidence and expert consensus, management recommendations for large vessel vasculitis have been formulated and are commended for use in everyday clinical practice.

EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases

Objectives To develop evidence-based European League Against Rheumatism (EULAR) recommendations for vaccination in patients with autoimmune inflammatory rheumatic diseases (AIIRD). Methods A EULAR task force was composed of experts representing 11 European countries, consisting of eight rheumatologists, four clinical immunologists, one rheumatologist/clinical immunologist, one infectious disease physician, one nephrologist, one paediatrician/rheumatologist and one clinical epidemiologist. Key questions were formulated and the eligible spectrum of AIIRD, immunosuppressive drugs and vaccines were defined in order to perform a systematic literature review. A search was made of Medline from 1966 to October 2009 as well as abstracts from the EULAR meetings of 2008 and 2009 and the American College of Rheumatology (ACR) meetings of 2007 and 2008. Evidence was graded in categories I–IV, the strength of recommendations was graded in categories A–D and Delphi voting was applied to determine the level of agreement between the experts of the task force. Results Eight key questions and 13 recommendations addressing vaccination in patients with AIIRD were formulated. The strength of each recommendation was determined. Delphi voting revealed a very high level of agreement with the recommendations among the experts of the task force. Finally, a research agenda was proposed. Conclusion Recommendations for vaccination in patients with AIIRD based on the currently available evidence and expert opinion were formulated. More research is needed, particularly regarding the incidence of vaccine-preventable infectious diseases and the safety of vaccination in patients with AIIRD.

EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs

Objectives To develop recommendations for the diagnosis, prevention and treatment of neuropsychiatric systemic lupus erythematosus (NPSLE) manifestations. Methods The authors compiled questions on prevalence and risk factors, diagnosis and monitoring, therapy and prognosis of NPSLE. A systematic literature search was performed and evidence was categorised based on sample size and study design. Results Systemic lupus erythematosus (SLE) patients are at increased risk of several neuropsychiatric manifestations. Common (cumulative incidence >5%) manifestations include cerebrovascular disease (CVD) and seizures; relatively uncommon (1–5%) are severe cognitive dysfunction, major depression, acute confusional state (ACS), peripheral nervous disorders psychosis. Strong risk factors (at least fivefold increased risk) are previous or concurrent severe NPSLE (for cognitive dysfunction, seizures) and antiphospholipid antibodies (for CVD, seizures, chorea). The diagnostic work-up of suspected NPSLE is comparable to that in patients without SLE who present with the same manifestations, and aims to exclude causes unrelated to SLE. Investigations include cerebrospinal fluid analysis (to exclude central nervous system infection), EEG (to diagnose seizure disorder), neuropsychological tests (to assess cognitive dysfunction), nerve conduction studies (for peripheral neuropathy) and MRI (T1/T2, fluid-attenuating inversion recovery, diffusion-weighted imaging, enhanced T1 sequence). Glucocorticoids and immunosuppressive therapy are indicated when NPSLE is thought to reflect an inflammatory process (optic neuritis, transverse myelitis, peripheral neuropathy, refractory seizures, psychosis, ACS) and in the presence of generalised lupus activity. Antiplatelet/anticoagulation therapy is indicated when manifestations are related to antiphospholipid antibodies, particularly thrombotic CVD. Conclusions Neuropsychiatric manifestations in SLE patients should be first evaluated and treated as in patients without SLE, and secondarily attributed to SLE and treated accordingly.

Effectiveness of Rituximab Treatment in Primary Sjogren's Syndrome A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE To study the efficacy and safety of B cell depletion with rituximab, a chimeric murine/human anti-CD20 monoclonal antibody, in patients with primary Sjögrens syndrome (SS) in a double-blind, randomized, placebo-controlled trial. METHODS Patients with active primary SS, as determined by the revised American-European Consensus Group criteria, and a rate of stimulated whole saliva secretion of > or =0.15 ml/minute were treated with either rituximab (1,000 mg) or placebo infusions on days 1 and 15. Patients were assigned randomly to a treatment group in a ratio of 2:1 (rituximab:placebo). Followup was conducted at 5, 12, 24, 36, and 48 weeks. The primary end point was the stimulated whole saliva flow rate, while secondary end points included functional, laboratory, and subjective variables. RESULTS Thirty patients with primary SS (29 female) were randomly allocated to a treatment group. The mean +/- SD age of the patients receiving rituximab was 43 +/- 11 years and the disease duration was 63 +/- 50 months, while patients in the placebo group were age 43 +/- 17 years and had a disease duration of 67 +/- 63 months. In the rituximab group, significant improvements, in terms of the mean change from baseline compared with that in the placebo group, were found for the primary end point of the stimulated whole saliva flow rate (P = 0.038 versus placebo) and also for various laboratory parameters (B cell and rheumatoid factor [RF] levels), subjective parameters (Multidimensional Fatigue Inventory [MFI] scores and visual analog scale [VAS] scores for sicca symptoms), and extraglandular manifestations. Moreover, in comparison with baseline values, rituximab treatment significantly improved the stimulated whole saliva flow rate (P = 0.004) and several other variables (e.g., B cell and RF levels, unstimulated whole saliva flow rate, lacrimal gland function on the lissamine green test, MFI scores, Short Form 36 health survey scores, and VAS scores for sicca symptoms). One patient in the rituximab group developed mild serum sickness-like disease. CONCLUSION These results indicate that rituximab is an effective and safe treatment strategy for patients with primary SS.

International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies

Anti-nuclear antibodies (ANA) are fundamental for the diagnosis of autoimmune diseases, and have been determined by indirect immunofluorescence assay (IIFA) for decades. As the demand for ANA testing increased, alternative techniques were developed challenging the classic IIFA. These alternative platforms differ in their antigen profiles, sensitivity and specificity, raising uncertainties regarding standardisation and interpretation of incongruent results. Therefore, an international group of experts has created recommendations for ANA testing by different methods. Two groups of experts participated in this initiative. The European autoimmunity standardization initiative representing 15 European countries and the International Union of Immunologic Societies/World Health Organization/Arthritis Foundation/Centers for Disease Control and Prevention autoantibody standardising committee. A three-step process followed by a Delphi exercise with closed voting was applied. Twenty-five recommendations for determining ANA (1–13), anti-double stranded DNA antibodies (14–18), specific antibodies (19–23) and validation of methods (24–25) were created. Significant differences between experts were observed regarding recommendations 24–25 (p<0.03). Here, we formulated recommendations for the assessment and interpretation of ANA and associated antibodies. Notably, the roles of IIFA as a reference method, and the importance of defining nuclear and cytoplasmic staining, were emphasised, while the need to incorporate alternative automated methods was acknowledged. Various approaches to overcome discrepancies between methods were suggested of which an improved bench-to-bedside communication is of the utmost importance. These recommendations are based on current knowledge and can enable harmonisation of local algorithms for testing and evaluation of ANA and related autoantibodies. Last but not least, new more appropriate terminologies have been suggested.

Antineutrophil cytoplasmic antibodies: A still-growing class of autoantibodies in inflammatory disorders

Antineutrophil cytoplasmic antibodies (ANCA) have been described as sensitive and specific markers for active Wegeners granulomatosis (WG). ANCA in WG produce a characteristic cytoplasmic staining pattern of neutrophils (c-ANCA) and are directed against proteinase 3 (Pr3), a serine protease from the azurophilic granules. c-ANCA, more or less equivalent to anti-Pr3, occur in more than 90% of patients with extended WG, in 75% of patients with limited WG without renal involvement, and in some 40% to 50% of patients with vasculitic overlap syndromes suggestive of WG such as microscopic polyarteritis. The presence of c-ANCA is highly specific for those diseases (greater than 98%). Changes of levels of c-ANCA precede disease activity and may be used as guidelines for treatment. Antibodies producing a perinuclear staining of ethanol-fixed neutrophils (p-ANCA) occur in a wide range of diseases. They are directed against different cytoplasmic constituents of neutrophils. Among those, antibodies to myeloperoxidase are found in patients with idiopathic crescentic glomerulonephritis, the Churg-Strauss syndrome, polyarteritis nodosa with visceral involvement, and vasculitic overlap syndromes. Their specificity for this group of necrotizing vasculitides is high (94% to 99%), although they may occur in patients with hydralazine-induced glomerulonephritis, anti-glomerular basement membrane disease, and possibly in some patients with idiopathic systemic lupus erythematosus. Antibodies to leukocyte elastase are incidentally found in patients with vasculitic disorders, whereas lactoferrin antibodies are detected in patients with primary sclerosing cholangitis with or without ulcerative colitis and in rheumatoid arthritis. Their diagnostic significance awaits further studies. p-ANCA of undefined specificity may distinguish ulcerative colitis (sensitivity of 75%) from Crohns disease (sensitivity of 20%). p-ANCA also occur in autoimmune liver diseases: in 75% of patients with chronic active hepatitis, in 60% to 85% of those with primary sclerosing cholangitis, and in about 30% of patients with primary biliary cirrhosis. Finally, p-ANCA are detected in chronic arthritides and in some 5% of healthy controls. Assessment of their diagnostic value has to await further characterization of the antigens involved, allowing the development of antigen-specific assays.

Leukocyte activation in sepsis; correlations with disease state and mortality

Objective: The immune response in sepsis shows a bimodal pattern consisting of an early, frequently exaggerated inflammatory response followed by a state of hyporesponsiveness often referred to as the compensatory anti-inflammatory response syndrome (CARS). Insight into the disease state may be helpful in deciding whether to choose immune stimulatory or anti-inflammatory therapy in these patients and may determine clinical outcome. We hypothesized that poor outcome in patients with sepsis is related to the severity of CARS, as reflected in the degree of leukocyte activation. Design: Prospective study. Setting: Intensive and respiratory care unit at a university hospital. Patients: Twenty consecutive patients with sepsis and 20 healthy age-matched volunteers. Interventions: None. Measurements and results: Analysis of surface expression of HLA-DR, CD11 b, ICAM-1, CD66 b, CD63 and CD64 on neutrophils and monocytes by flow cytometry and determination of plasma concentrations of lactoferrin, interleukin 6 and neopterin by ELISA at the time of diagnosis. Patient data were related to those of controls; moreover patient data between survivors and non-survivors were compared. Increased expression of all markers, except HLA-DR, was observed on both neutrophils and monocytes from patients compared to healthy controls. HLA-DR expression on monocytes was significantly decreased in patients with sepsis (p < 0.01). Expression of CD11 b and HLE on neutrophils, and ICAM-1 on monocytes, were lower in patients who died compared to those who survived (p < 0.05). Conclusion: In sepsis, both neutrophils and monocytes are activated compared to healthy controls. Poor prognosis is associated with a lower expression of activation markers on monocytes and neutrophils, suggesting that poor outcome in these patients may be due to the compensatory anti-inflammatory response.