[The significance of health-related quality of life in systemic vasculitides]. / Bedeutung der gesundheitsbezogenen Lebensqualität bei systemischen Vaskulitiden.

Systemic vasculitides are a heterogenous group of chronic relapsing diseases. Initial data show that health-related quality of life (HRQoL) from the patient's perspective is reduced on all levels (physical, social and emotional). These studies suggest that generic questionnaires do not encompass all relevant and important levels of HRQoL in vasculitis. Moreover, data indicate that tiredness (fatigue) and reduced energy levels play a significant role. This article presents an overview of the existing literature.

Single cell analysis of B lymphocytes from Wegener's granulomatosis: B cell receptors display affinity maturation within the granulomatous lesions.

Increased amounts of anti-neutrophil cytoplasm antibody (ANCA) directed against proteinase 3 (PR3) are a diagnostic and pathogenic hallmark of full-blown Wegener's granulomatosis (WG). Aggregates of B lymphocytes proximal to PR3+ cells as well as plasma cells have been described as substantial components of Wegener's granuloma and could participate in forming tertiary lymphoid structures, which might promote autoantibody formation. Our aim was a molecular analysis of single B cells in order to develop a methodological approach that allows examination of potential ANCA formation in the tissue. Single B cells from cryo-conserved endonasal biopsies of three WG patients were isolated, using laser-assisted microdissection. Subsequently, their immunoglobulin variable heavy (VH) and light (Vkappa, Vlambda) chain genes were analysed by single cell polymerase chain reaction and direct sequencing. Sixteen immunoglobulin VH-Vkappa or VH-Vlambda chain gene couples were characterized. Twelve of these immunoglobulin gene couples resembled memory B cells. Two offsprings of one B cell were detected, indicating clonal expansion. VH genes representing 39 single B cells of WG tissues displayed significantly more mutations when compared with VH genes from peripheral blood of a healthy donor. The findings confirm and extend our previous results, arguing for an initial selection and affinity maturation of B cells within Wegener's granuloma. Further, the methodology provides the initial basis for the recombinant generation of antibodies derived from tissue cells.

Birmingham vasculitis activity score, disease extent index and complement factor C3c reflect disease activity best in hepatitis C virus-associated cryoglobulinemic vasculitis.

OBJECTIVE: Clinical measures of vasculitis activity (Birmingham vasculitis activity score = BVAS) and disease extent (Disease Extent Index = DEI), serological and immunological parameters were evaluated for the monitoring of hepatitis C virus (HCV)-associated cryoglobulinemic vasculitis (CV), treated with either cyclophosphamide or interferon-alpha 2b depending on disease severity. METHODS: Serial serum samples of 15 patients with HCV-associated CV were analyzed, and BVAS, DEI, serological and immunological parameters were recorded at diagnosis and during therapy. Eight patients were treated with interferon-alpha 2b and 7 patients with cyclophosphamide. RESULTS: A complete or partial response of the CV was seen in both treatment groups. BVAS, complement factor C3c, cryoglobulinemia, and rheumatoid factor significantly decreased in both treatment groups during 6 months (p < 0.05). DEI decrease was significant in the cyclophosphamide group (p < 0.05), and there was a trend in the interferon-alpha 2b group (p = 0.06). BVAS and DEI were significantly positively correlated, and both parameters were significantly negatively correlated with C3c levels in both treatment groups (interferon-alpha 2b/cyclophosphamide: r = -0.89, p = 0.001 versus r = -0.87, p < 0.001, respectively) whereas other parameters were not, e.g. ESR and CRP. CONCLUSIONS: Patients with different degrees of disease severity, treated with either cyclophosphamide or interferon-alpha 2b depending on their disease activity, achieved remission of their CV. BVAS, DEI and C3c were especially useful in the follow-up of HCV-associated CV. C3c correlated with BVAS and DEI during therapy and provided additional information about vasculitis activity that was not reflected by other serological or immunological parameters, e.g. ESR or CRP.

ANCA against bactericidal/permeability-increasing protein, azurocidin, calprotectin and defensins in rheumatic and infectious diseases: prevalence and clinical associations.

OBJECTIVE: To determine the prevalence and clinical associations of ANCA against the antibiotic proteins and peptides: Bactericidal/permeability-increasing protein (BPI), Azurocidin (AZ), Calprotectin (CP) and beta-Defensin-1 and -2 (DF). METHODS: Patients with ANCA-associated vasculitides (n = 99), other vasculitides and rheumatic connective tissue diseases (n = 303), HIV-infection (n = 66), other infectious diseases (n = 134) Crohn's disease (n = 12) and ulcerative colitis (n = 12) were tested for BPI-, AZ-, CP-, DF-, PR3-, and MPO-ANCA in indirect immunofluorescence technique (IFT) and ELISA. RESULTS: In ANCA associated vasculitides BPI-ANCA were detected in 6% of patients. In HIV infection, BPI was the main target antigen of ANCA-IFT positive sera (74%). BPI-ANCA was associated with higher inflammatory activity. In Crohn's disease and ulcerative colitis BPI-ANCA was prominent (34% of patients). AZ-ANCA were found in 5% of patients. No ANCA were detected against defensin and calprotectin. CONCLUSION: BPI-ANCA is the main autoantibody in HIV and is associated with higher inflammatory activity. In inflammatory bowel diseases BPI-ANCA is predominant, AZ-ANCA are also present to a lesser extend. Both were not useful characterize clinical subgroups. No ANCA were detected against calprotectin or defensins.

Development and validation of a disease extent index for Wegener's granulomatosis.

AIMS: The quantitative assessment of disease extent (staging) and activity (grading) in patients with ANCA-associated vasculitides is one prerequisite for the comparison of outcomes in different patient cohorts. We present a validation study of the Disease Extent Index (DEI). METHODS: 66 patients with Wegener's granulomatosis were examined to assess the validity, reliability and sensitivity to change of the DEI. Correlation coefficients were calculated to estimate associations between DEI and BVAS (Birmingham Vasculitis Activity Score), a previously established activity score, and between DEI and serological markers. RESULTS: Among patients with active disease, DEI correlated significantly with cANCA titer (r = 0.46), leukocyte count (r = 0.38) and platelet count (r = 0.53). Among patients in remission, DEI correlated significantly with cANCA titer (r = 0.61), CRP (r = 0.47) and sIL2R (r = 0.47). Additionally, a high association of DEI and BVAS (r = 0.9) confirmed a rather high convergent validity. The effect size of DEI equals 2.37 standard deviation units and indicates a considerable change from active disease to remission. CONCLUSIONS: The DEI is valid, reliable, easy, quick to perform and highly reproducible. Although it correlates with some surrogate markers of disease activity and the BVAS, the DEI quantifies different domains of the disease than the BVAS and should therefore be used in conjunction with the BVAS.

[Longitudinal effects of structured patient education programs for vasculitis patients]. / Longitudinale Effekte des strukturierten Patientenschulungsprogramms für Vaskulitispatienten.

According to the literature it is known that structured standardized patient education represents an effective additional treatment in patients with chronic diseases. Positive effects in the reduction of disease activity and depression have been shown for rheumatoid arthritis, systemic lupus erythematodes, and diabetes mellitus. An interdisciplinary approach for providing information was developed for patients with primary systemic vasculitides (PSV) in the vasculitis center in Bad Bramstedt. The contents of the seminars were revised and condensed into five modules. To evaluate the new form of the program a documentation system was designed. Patients were trained in closed groups (n=10-15) and completed the questionnaires at baseline, 4 weeks, 6 and 12 months following participation. A total of 102 patients in 10 closed groups showed a statistically significant increase in their knowledge in the three aspects of medicine, therapy and side effects, nutrition and physiotherapy. Health-related quality of life in all dimensions increased considerably. Both self-efficacy and the patient-assessed health status improved. The standardized structured education program for vasculitis patients provides an additional treatment in the interdisciplinary care of vasculitis.

[B lymphocyte differentiation in granulomatous tissues of the lung and the nasal mucosa in Wegener's granulomatosis: origin of anti-neutrophil cytoplasmic antibody formation?]. / B-Lymphozyten-Differenzierung in granulomatösen Geweben der Lunge und der Nasenschleimhäute beim Morbus Wegener: Ursprungsort der ANCA-Bildung?

Wegener's granulomatosis (WG) starts with granulomatous inflammation of the respiratory tract before it converts into a potentially organ and life threatening systemic vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA). The site of formation of the highly specific ANCA directed against "Wegener's autoantigen" proteinase 3 (PR3) is still unknown. Previously, we have shown that follicle-like B lymphocytic infiltrates in the vicinity to PR3 expressing cells in WG-granulomata. We characterized the immunoglobulin-VH repertoire in lung and nasal granulomata (paraffin embedded) from four WG patients. A total of 115 individual VH genes were characterized and compared to 84 VH genes from the peripheral blood of a healthy donor. We found an increased frequency of mutations with a bias to amino acid exchanges within the antigen binding sites (CDR) 1 and 2 in WG tissue. A large number of mutations led to negatively charged amino acids and may increase affinity to the positively charged PR3. Furthermore, the occurrence of differently mutated members of one B cell clone indicates clonal expansion and intraclonal diversification by an antigen, e.g. PR3. Several WG tissue derived genes displayed similarities to published sequences from peripheral PR3 ANCA producing B cells. Thus, granulomata of the lower and upper respiratory tract contain follicle-like B cell clusters with a selected VH repertoire infiltrate in WG. WG granulomata could be the place of autoantigen presentation and formation of high-affinity ANCA within neoformed ectopic or tertiary lymphoid-like tissue areas.

B lymphocyte maturation in Wegener's granulomatosis: a comparative analysis of VH genes from endonasal lesions.

BACKGROUND: Anti-neutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) are highly specific for Wegener's granulomatosis (WG). Evidence for a pivotal role of PR3-ANCA in the induction of vasculitis has been demonstrated. B cell clusters have been observed within endonasal biopsy specimens. OBJECTIVES: To determine whether B cell selection and maturation take place in granulomatous lesions of WG. METHODS: Granulomatous lesions and the immunoglobulin (VH) gene repertoire from nasal tissue of six WG patients-two active and two smouldering localised WG (ANCA negative, restricted to respiratory tract), plus one active and one smouldering PR3-ANCA positive generalised WG-were characterised by immunohistochemistry, polymerase chain reaction, cloning, DNA sequencing and database comparison. RESULTS: B lymphocyte-rich, follicle-like areas were observed proximal to PR3 positive cells and plasma cells in granulomatous lesions; 184 VH genes from these granulomatous lesions were compared with 84 VH genes from peripheral blood of a healthy donor. The mutational pattern of VH genes from active WG resembled memory B cells. Structural homologies of VH genes from granulomatous lesions to PR3-ANCA encoding genes were detected. Significantly more genes (55%, 45%, and 53%, respectively) from active WG compared with the healthy repertoire carried mutations to negatively charged amino acids within the binding site coding regions, favouring affinity to the positively charged PR3. CONCLUSIONS: Selection and affinity maturation of potentially PR3-ANCA producing autoreactive B cells may start in granulomatous lesions, thereby contributing to disease progression from ANCA negative localised to PR3-ANCA positive generalised WG.

[A new training program--a status report: vasculitis]. / Ein neues Schulungsprogramm-ein Statusbericht: Vaskulitis.

Referring to the literature, it is known that structured standardized patient education represents an effective additional treatment in patients with chronic diseases. Programs are based on cognitive behavioral interventions. Within the last years an interdisciplinary approach for providing information on disease, therapies, side effects, coping strategies, nutrition and physiotherapy has been developed for patients with primary systemic vasculitides (PSV) in the vasculitis center Medical University of Luebeck/Bad Bramstedt. The contents of the seminars were revised and condensed into five modules. To evaluate the new program a documentation system consisting of patient and physician-administered questionnaires assessing socioeconomic, knowledge and disease-related outcome-parameters has been designed. Patients completed the questionnaires at baseline, 4 weeks, 6 and 12 months after training. First results show statistically significant improvement of knowledge and health-related quality of life.

[Interdisciplinary management of vasculitis patients: internist/rheumatologist]. / Interdisziplinäre Betreuung von Vaskulitis-Patienten: Der Internist/Rheumatologe.

Systemic vasculitides (SV) represent a heterogeneous group of different entities with varying clinical and pathological-anatomical characteristics that physicians of diverse disciplines are involved in the treatment of patients with SV. At the onset of disease organ manifestations often present as a single symptom without appearance of indirect signs of vasculitides as musculoskeletal complaints and constitutional symptoms indicating inflammatory systemic disease. Therefore early interdisciplinary care is extremely important to avoid major organ involvement with the development of fatal disease. Besides the multidisciplinary physical examination serological and immunological parameters, particularly in small vessel vasculitides are relevant in establishing the diagnosis. Regarding the interdisciplinary care we differentiate between primary diagnostic procedures and continuous follow-up to observe therapeutic and side effects of medications. Instruments for the assessment of disease extent (DEI), activity (BVAS) and irreversible damage (VDI) were developed in recent years to document prospectively the disease status and support activity-adjusted treatment. Because of the chronic relapsing character of systemic vasculitides, the measurement of health-related quality of life gained progressive interest in the longitudinal follow-up. In addition in these rare diseases early patient education with information on the disease, treatment, side effects and training in self management strategies will enable patients to actively participate in the management of their disease and bear responsibility.

[Long-term prognosis and outcome of patients with primary systemic vasculitis: initial results in Germany]. / Langzeitprognose und -outcome von Patienten mit primär systemischen Vaskulitiden (PSV): Erste Ergebnisse in der BRD.

Some outcome parameters have been shown to represent valuable measures for the long-term assessment of primary systemic vasculitides (PSV). These parameters include disease extent, disease activity, damage, and the health-related quality of life. We describe a concept for the establishment of a detailed documentation system for PSV with a duration of at least 5 years to obtain a reliable characterization of these patients. This database will provide the basis for a PSV cohort and the development of an interdisciplinary patient education concept followed by an evaluation with a multicenter, trial.

[Scientifically based patient education exemplified by patients with primary systemic vasculitis. The vasculitis patient education program--development, contents and initial results of evaluation]. / Wissenschaftlich begründete Patientenschulung am Beispiel der Patienten mit primär systemischen Vaskulitiden. Das Vaskulitis-Schulungsprogramm--Entwicklung, Inhalte und erste Ergebnisse der Evaluation.

Referring to the literature, it is known that structured standardized patient education represents an effective additional treatment in patients with chronic diseases. Most programs are based on cognitive behavioral interventions. Within the last few years, an interdisciplinary approach for providing information on disease, therapies, side effects, coping strategies, nutrition and physiotherapy has been developed for patients with primary systemic vasculitides (PSV) in the vasculitis center of the Medical University of Lübeck/Bad Bramstedt. The contents of the seminars were revised and condensed into five modules. New slides and handouts for patients were developed. To evaluate the new form of the program, a documentation system consisting of patient and physician-administered questionnaires assessing socioeconomic, knowledge and disease-related outcome-parameters was designed. Patients are trained in closed groups (n = 10-15) and asked to complete questionnaires at baseline, 4 weeks and 6 months after training. First results show statistically significant improvement of knowledge and health-related quality of life.

[A new patient education program: vasculitis]. / Ein neues Schulungsprogramm. Ein Statusbericht: Vaskulitis.

Referring to the literature it is known that structured standardized patient education represents an effective additional treatment in patients with chronic diseases. Programs base on cognitive behavioral interventions. Within the last years an interdisciplinary approach for providing information on disease, therapies, side effects, coping strategies, nutrition and physiotherapy has been developed for patients with primary systemic vasculitides (PSV) in the vasculitis center Medical University of Luebeck/Bad Bramstedt. The contents of the seminars were revised and condensed into five modules. To evaluate the new program a documentation system consisting of patient and physician- administered questionnaires assessing socioeconomic, knowledge and disease-related outcome-parameters has been designed. Patients completed the questionnaires at baseline, 4 weeks, 6 and 12 months after training. First results show statistically significant improvement of knowledge and health-related quality of life.

[Patient "satisfaction" in medical rehabilitation--a useful outcome indicator?]. / Patienten-"Zufriedenheit" in der medizinischen Rehabilitation--ein sinnvoller Outcome-Indikator?

Within the context of a five-part quality assurance programme for rehabilitation hospitals issued by the German Association of Statutory Pension Scheme Underwriters (Verband Deutscher Rentenversicherungsträger) we developed a multisectional questionnaire to assess patient satisfaction with rehabilitation measures. This questionnaire records the patients' perceptions and ratings of rehabilitation structures and processes as well as the results of then. The article describes basic positions, chances and risks of assessing this measure of satisfaction as well as the development of our questionnaire. The dimensions of patients satisfaction are based on the differentiation between various sectors of clinical output and capacity (Leistungsbereiche) und demands on medical service and capacity (Leistungsansprüche). The questionnaire includes rating and reporting questions. Since it will be complemented by a second part on health outcomes, this "research tool" will be used routinely to compare hospitals on the basis of an annual random sample (15%) of all rehabilitation patients.

Long-term tolerability of methotrexate at doses exceeding 15 mg per week in rheumatoid arthritis.

The objective of this study was to examine longitudinally the tolerability of methotrexate (MTX) treatment at doses exceeding 15 mg/week in an open-label, prospective study. One hundred and eighty-five patients with rheumatoid arthritis were randomized to receive 15 mg or 25 mg MTX per week initially, and were followed over 30 months. Subsequent dose adjustments according to efficacy and tolerability resulted in levelling off of the mean dose at 18 mg/week, and the original treatment groups were combined for a longitudinal study comparing toxic events during months 1-12 and months 13-30. Withdrawals due to side-effects amounted to 17% during months 1-12 and 4% during months 13-30; dose reductions due to side-effects were 9% and 7%, respectively. The annual incidence of gastrointestinal side-effects increased from 26% to 39% (P = 0.05), that of liver enzyme elevation dropped from 43% to 10% (P < 0.001) and haemocytopenia remained stable at 5% and 7%. MTX pneumonitis was only observed during the first year, while airway complaints without evidence of parenchymal lung involvement increased to 10% beyond the first year. Fifty-six patients experienced 65 major infectious episodes over the 30-month period, with the respiratory tract being the most frequent site. This study showed that MTX treatment at doses exceeding 15 mg/week is tolerated over extended period of time. Major toxicity and withdrawals due to side-effects occurred predominantly during the first year of treatment and thus showed a decreasing trend over time, while minor toxic events continued throughout the study with a progressive rate of mucous membrane toxicity. MTX-treated RA appears to be a risk situation for major infection.

Immunological and clinical follow up of hepatitis C virus associated cryoglobulinaemic vasculitis.

OBJECTIVE: To study immunological markers and compare these markers with standard measures for the clinical and immunological follow up of vasculitis activity in hepatitis C virus (HCV) associated cryoglobulinaemic vasculitis (CV). METHODS: Serial serum samples from eight patients with newly diagnosed HCV associated CV were followed during interferon alpha treatment induced remission of the CV. Vasculitis activity and disease extent were evaluated with the Birmingham vasculitis activity score (BVAS) and disease extent index (DEI). Cryoglobulinaemia, complement levels (C3c, C4, and CH50), rheumatoid factor (RF), autoantibodies such as antinuclear antibodies, soluble interleukin 2 receptor (sIL2r), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble CD30 (sCD30) were determined. RESULTS: All patients achieved either complete or partial remission of their CV during interferon alpha treatment. There was a significant reduction in vasculitis activity and disease extent (BVAS, DEI), cryoglobulinaemia, RF, sIL2r, sICAM-1, and sCD30. Complement C3c levels increased significantly during this period. Erythrocyte sedimentation rate and levels of complement C4 and CH50 did not change significantly. Both clinical measures (BVAS and DEI) correlated significantly only with C3c and sCD30. CONCLUSIONS: Although this study was of only a small group of patients, it shows that BVAS and DEI as clinical measures and C3c and sCD30 as immunological markers may be useful in the follow up of disease activity of HCV associated CV. The data indicate that activity of the humoral (cryoglobulinaemia, RF, autoantibodies) and cellular (sIL2r, sICAM-1, sCD30) immune response and endothelial damage (sICAM-1) are found in HCV associated CV.

No difference in the incidences of vasculitides between north and south Germany: first results of the German vasculitis register.

OBJECTIVE: To register all newly diagnosed patients with primary systemic vasculitis (PSV) in two large regions in north and south Germany. METHODS: Between 1 January 1998 and 31 December 1999, all newly diagnosed cases of PSV, as defined by the Chapel Hill Consensus Conference 1992, were identified in two large mixed rural/urban regions in north and south Germany with a combined population of 4,880,543, for a population-based prospective study. The following sources were used: (i) all departments of every hospital, including their out-patient clinics; (ii) all departments of pathology; and (iii) all reference immunological laboratories serving the catchment area. All cases were re-evaluated by the authors. RESULTS: Over the whole period, 473 individuals were registered as having a new PSV. The incidence rates for all PSV were 54 cases per 1,000,000 inhabitants in the north and 48 in the south in 1998, and 48 and 41 respectively in 1999. People 50 yr and older had a three- to five-fold higher risk of getting PSVs than those under 50 yr. The incidences of antineutrophil cytoplasmic antibody (ANCA)-associated PSVs [Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS)] remained stable in both regions, at about 9.5 per 1,000,000 annually. The incidence of WG was two to three times greater than those of MPA and CSS. There was no difference in incidence rates between north and south Germany. CONCLUSION: First results from a population-based vasculitis register serving nearly 5,000,000 inhabitants in north and south Germany revealed no regional differences in the incidence of all PSVs between north and south. The incidence rates of ANCA-associated PSVs, such as WG and MPA, were lower than those in the UK and Norway but higher than that in Spain.