Gustatory and olfactory function in patients with granulomatosis with polyangiitis (Wegener's).

OBJECTIVES: Recent findings suggest that autoimmune disorders predispose to a diminished capacity to taste and smell. This has been shown for patients with systemic lupus erythematosus as well as for patients with rheumatoid arthritis (RA). Granulomatosis with polyangiitis (GPA), with its particular manifestations in the upper respiratory tract, may therefore have an even higher impact on these senses. The aims of this study were to evaluate the gustatory and olfactory function in patients with GPA, to compare them to sex- and age-matched healthy controls, and to correlate these findings with their GPA disease severity. METHOD: Patients with established GPA were analysed by standardized assessments for gustatory and olfactory functions and examined for disease activity, stage of disease, and treatment. RESULTS: Forty-four GPA patients were tested for their chemosensory functions. Compared to age- and sex-matched healthy controls, GPA patients showed significantly decreased olfactory scores along with diminished scores for their gustatory functions. The diminished sense of smell in GPA patients correlated significantly with elevated C-reactive protein (CRP) values whereas the gustatory impairment correlated with the duration and extent of the disease. CONCLUSIONS: Our results indicate that olfactory and gustatory functions are significantly decreased in GPA. As the olfactory function of these patients was comparable to patients with RA, chemosensory impairment may not simply be a consequence of the involvement of the upper respiratory tract, but rather a common complication of systemic autoimmune diseases.

[What factors determine the direct medical costs of patients with systemic lupus erythematosus in Germany? Subanalysis of the LUCIE study]. / Welche Faktoren bestimmen die direkten Krankheits-kosten bei Patienten mit Systemischem Lupus Erythe-matodes in Deutschland? - Subanalyse der LUCIE-Studie.

OBJECTIVES: The aim of this study was to evaluate annual direct medical costs of adult SLE patients with active autoantibody positive disease on medication in Germany. METHODS: A multicentre, observational, retrospective European study with German sub-analysis was performed. Costs were assessed according to national tariffs. RESULTS: 10 German centres included 77 patients. The mean (SD) annual direct medical costs of patients were € 3 452.21 (3 777.07), and were 3.4 times higher in severe than non-severe patients (€ 5 291.07 vs. 1 564.97; p<0.001). Cost of medication (€ 2 349.40) represented 68.1% of the total cost. Flares, especially severe flares, were identified as cost predictors. Each flare increased the annual total cost by € 2 164,01 (p<0,001). CONCLUSION: The annual direct medical cost of SLE patients in Germany is linked to disease severity. Medical treatments and severe flares were identified as the cost predictors and drivers, respectively.

[Hypertrophic osteoarthropathy. Bamberger-Marie disease]. / Hypertrophe Osteoarthropathie. Marie-Bamberger-Syndrom.

Hypertrophic osteoarthropathy (HOA) is the classical neoplastic disease in rheumatology characterized by a combination of digital clubbing, joint and bone pain, and proliferative periostitis. This combination of symptoms should initiate an intensive search for an underlying malignant disease usually of thoracic organs. Here we report the case of a patient with HOA and neuroendocrine carcinoma of the esophagus. Other non-malignant disorders of the lungs, heart and other organs should be considered in the differential diagnosis. In addition, rare cases of a primary hereditary form of HOA exist and the genetic background has recently been discovered. Thus, new insights into the pathophysiology have improved diagnostic and therapeutic options for this disorder.

Disease activity and damage accrual during the early disease course in a multinational inception cohort of patients with systemic lupus erythematosus.

An inception cohort of patients with systemic lupus erythematosus from 14 European centres was followed for up to 5 years in order to describe the current early disease course. At inclusion patients (n = 200, 89% female, mean age 35 years, 97% Caucasian, mean SLEDAI 12.2) fulfilled a mean of 6.5 ACR classification criteria. The most prevalent criteria were antinuclear Ab presence (97%) followed by anti-dsDNA Ab (74%), arthritis (69%), leukocytopenia (54%) and malar rash (53%), antiphospholipid Ab (48%) and anti-synovial membrane Ab (21.6%). Clinical signs of lupus nephritis (LN) were present in 39% with biopsy-confirmed LN seen in 25%. Frequent additional findings were hypocomplementaemia (54%), anti-SSA Ab (49%), alopecia (26%) and Raynaud's phenomenon (31%). There were few regional differences in disease presentation and management. One and 5-year survival rates were 99% and 97% respectively. During the mean follow-up of 4.1 years 25% entered a state of early disease quiescence by global physician assessment, but the overall risk of subsequent flare was 60%. Maximum SLEDAI scores decreased over time, but 45% of patients accrued damage (SDI >or=1) for which baseline presence of proteinuria and persistent disease activity were independent predictors. The results indicate minor differences in SLE presentation and treatment within various regions of Europe and a high diagnostic reliance on anti-dsDNA Ab. Despite early reductions in disease activity and improved mortality, the risk for disease flare and damage development is, however, still substantial, especially in patients not entering an early remission.

Rare monogenetic syndromes in rheumatology practice.

The EULAR Executive Committee defined eight overall objectives for EULAR to achieve by 2012. The first of these objectives is to strengthen activities in areas that are currently less prioritized, such as non-inflammatory and orphan diseases. This study aims to increase awareness of rheumatologists towards rare hereditary musculoskeletal disorders, by describing their genetics, pathogenesis, and typical clinical and radiological features. We analyzed patient charts from the recent 5 years from the Rheumatology Outpatient Department of the University Erlangen-Nuremberg and of two rheumatologic practices, all joined in a regional network ("Rheumazentrum Erlangen") retrospectively for hereditary musculoskeletal disorders other than hemochromatosis, autoinflammatory syndromes, lysosomal storage diseases, and hypermobility syndromes. We were able to identify four patients with trichorhinophalangeal syndrome type I, multiple exostoses, Kirner's deformity, and osteopoikilosis. In addition, a PubMed and OMIM ("Online Mendelian Inheritance in Man") database search was carried out using these as key words and all relevant articles were reviewed for each of these diseases. Our findings show that rare hereditary musculoskeletal disorders occur in a routine rheumatological setting and that rheumatologists should know the clinical and radiological features of these diseases in order to adequately counsel the patient.

Telomere length analysis in monocytes and lymphocytes from patients with systemic lupus erythematosus using multi-color flow-FISH.

In order to analyse telomere length in subsets of human peripheral blood lymphocytes and monocytes, we modified a recently developed multicolor flow- fluorescent in situ hybridization (FISH) methodology that combines flow-FISH and antibody staining for cell surface antigens. We analysed telomere length of peripheral blood mononuclear cells in a group of 22 patients with systemic lupus erythematosus (SLE) and 20 age-matched healthy donors. We found that neither CD4+, CD8+, CD19+ cells nor CD14+ monocytes have significantly shorter telomeres compared with their healthy counterparts. On the basis of these findings, we then used monocyte telomere length as internal reference in order to control for intra-individual variability in telomere length. By using this approach, we could demonstrate significant telomere shortening in all three lymphocyte subsets (in all cases P < 0.05) compared with monocytes. However, these differences did not vary significantly between SLE patients and controls. In summary, telomere lengths in subpopulations of hematopoietic cells can be monitored in patients with SLE using multicolor flow-FISH. While confirming data by other groups on telomere length in lymphocyte subpopulations, our data argue against an increased proliferation rate of peripheral blood monocytes reflected by accelerated telomere shortening in patients with SLE.

Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener's granulomatosis.

OBJECTIVES: Results from open-label trials suggest that methotrexate (MTX) and leflunomide (LEF) are effective for maintenance of remission in Wegener's granulomatosis (WG), but data from randomized controlled clinical trails are not yet available. METHODS: In this multicentre, prospective randomized controlled clinical trial, patients with generalized WG were treated either with oral LEF 30 mg/day or oral MTX (starting with 7.5 mg/week reaching 20 mg/week after 8 weeks) for 2 yrs following induction of remission with cyclophosphamide. The primary endpoint was the incidence of relapses. Secondary outcome parameters were DEI, BVAS, SF-36, cANCA-titre, ESR and CRP. RESULTS: Fifty-four patients were included in the study, 26 in the LEF-limb, 28 in the MTX-limb. In the LEF-group, six patients relapsed after a median time of 7 months, thereof one major relapse with a new pulmonary manifestation. In the MTX-group, 13 relapses occurred in 6 months, of which seven were major: rapidly progressive glomerulonephritis (n = 4), pulmonary haemorrhage (n = 2) and one cerebral granuloma. The significantly higher incidence of major relapses in the MTX-limb (P = 0.037) led to premature termination of the study. In the LEF-limb, four patients were withdrawn due to hypertension (n = 2), peripheral neuropathy (n = 1) and leucopenia (n = 1). CONCLUSION: LEF at a dosage of 30 mg/day appears to be effective in the prevention of major relapses in WG, however, this is associated with an increased frequency of adverse events. Further studies testing other dosing regimens of lower doses of LEF are needed to confirm these promising results in larger patients cohorts.

Treatment of hereditary angioneurotic oedema (HANE) with tibolone.

OBJECTIVE: Eight women, aged 25-58 years, with hereditary angioneurotic oedema (HANE) were treated with tibolone, a synthetic steroid exhibiting oestrogenic, androgenic and progestational activity. DESIGN: Pilot study. RESULTS: Tibolone at a dose of 2.5-7.5 mg/day significantly reduced the number and severity of attacks and the number of ampoules of C1-esterase inhibitor (C1-INH) needed for symptomatic therapy. The efficacy of tibolone was comparable to that of danazol, while the androgenic side-effects were considerably reduced. CONCLUSIONS: Tibolone may represent an alternative to danazol administration for the prophylaxis of HANE in women.

[Glucocorticoid therapy in collagen diseases diseases]. / Glucocorticoidtherapie bei Kollagenosen.

Glucocorticoids are irreplaceable for the treatment of connective tissue diseases due to their strong and rapid anti-inflammatory and immuno-modulatory effects. Its use and their dosage depend on the activity of the disease and organ manifestations. There is no alternative to high doses, often even as intravenous pulse therapy, in life-threatening situations with imminent organ failure. Despite an additional immuno- suppressive medication, glucocorticosteroids are mandatory for long-term treatment in most cases. In special situations like high age, gravity or comorbidities like renal failure or hepatosis, glucocorticosteroids are the option with the least possible potential for complications. In the future, new corticosteroids and steroid sparing immuno-suppressants like biologics will be able to reduce the spectrum and the severity of corticoid-induced side effects. Modern state-of-the-art therapeutic regimens for patients with connective tissue diseases should not only be able to sufficiently control the disease activity but also include the prophylaxis of associated comorbidities like arteriosclerosis, osteoporosis or infections.

Factors associated with coronary artery calcification in young female patients with SLE.

BACKGROUND: With improved survival rates of patients with systemic lupus erythematosus (SLE), damage such as accelerated atherosclerosis gains increasing importance. OBJECTIVE: To identify the prevalence of coronary artery calcifications (CAC) in asymptomatic patients. METHODS: Electron beam tomography (EBT) was performed in 75 female patients with SLE aged <50. The results were correlated with traditional and SLE related factors associated with CAC. 49 women with symptomatic coronary heart disease (CHD) and 279 women without CHD were also analysed. RESULTS: Overall, 21/75 (28%) patients had CAC. Low HDL cholesterol levels <1.40 mmol/l (p=0.03, OR=1.8, 67% v 39%) and cigarette smoking (p=0.01, OR=5.7, 76% v 44%) were identified as factors associated with CAC. Hypertension and high cholesterol were more common in women with CHD (p<0.01) than in those without CHD. SLE related factors were proteinuria (1331 v 465 mg/day, p=0.02), impaired renal function (p=0.02, OR=2.6, 26% v 6%), and high C3 levels (p=0.04, OR=1.8, 65% v 38%). High C3 levels were also more common in symptomatic CHD (p=0.02). The prevalence of Sm antibodies was lower in patients with CAC (15% v 42%, p=0.03). In a multivariate analysis, cigarette smoking, reduced renal function, high C3, and a cumulative steroid dose above 30 g were the most important CAC associated factors in the lupus cohort. CONCLUSION: A subgroup of patients with SLE with CAC without any clinical symptoms of CHD was identified by EBT. Therefore, EBT is useful for assessing asymptomatic atherosclerosis in this group.

[TNF alpha-antagonists in collagen vascular disease]. / Gibt es eine Indikation für TNF alpha-Antagonisten bei Kollagenosen?

Over the last ten years various biologics have been introduced in the therapy of rheumatic diseases. The most successful approach so far has been the inhibition of TNF alpha, which is able to suppress systemic inflammation in an unprecedented manner. However, the early observation of newly developed antinuclear antibodies and some cases of drug-induced lupus has so far hampered the evaluation of this treatment option in larger clinical studies for collagen vascular diseases. Thus, ten years after treating the first RA patients with TNF alpha-Blockers we still only have reports of individual cases of patients with collagen vascular diseases treated with this principle. The following article reviews these single cases and summarizes the current knowledge about efficacy and safety of anti-TNF alpha-therapy for this indication.

Definition of risk factors for death, end stage renal disease, and thromboembolic events in a monocentric cohort of 338 patients with systemic lupus erythematosus.

BACKGROUND: The survival rate in patients with systemic lupus erythematosus (SLE) has improved dramatically during the past four decades to 96.6% (five year) in the Erlangen cohort, but it is nearly three times as high as in an age and sex matched control population. Reasons for death are mainly cardiovascular diseases (37%) and infections (29%). OBJECTIVE: To find risk factors existing at disease onset for a severe outcome in the Erlangen cohort. PATIENTS AND METHODS: By using a database of 338 patients with SLE from a single centre, documented at least one to 15 years and including Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage score data and index (SDI) and an activity score (European Consensus Lupus Activity Measurement (ECLAM)), a retrospective search was made for risk factors for a severe outcome like death, end stage renal disease (ESRD), and thromboembolic events (TE) in SLE. For this purpose, multivariable Cox regression models were analysed using the statistical package SPSS 10.0 for Windows. RESULTS: The following were defined as risk factors for death at disease onset: male sex (p<0.001, relative risk (RR)=3.5), age >40 at disease onset (p<0.0001, RR=19.9), nephritis (p<0.05, RR=1.6), a reduction of creatinine clearance (p<0.001, RR=1.8), heart disease (p=0.05, RR=1.5), and central nervous system (CNS) disease (p=0.06, RR=1.6). An increase in the SDI of two or more points from the first to the third year of disease was the worst prognostic factor (p<0.0001, RR=7.7). The existence of Ro or nRNP antibodies, or both, was protective (p<0.05, RR =0.1). A low C3 (p<0.01 RR=3.0) and splenomegaly (p<0.01 RR=2.7) at disease onset turned out to be risk factors for ESRD besides a nephritis. In patients with hypertension (p<0.05) and/or high titres of dsDNA antibodies (>70 U/l) (p<0.01) and/or a mean ECLAM score of 4 (p<0.01) in the course of disease, a prevalence of ESRD was recorded in 9% (p<0.05) and 10% (p<0.01), and 8% (p<0.01) v 4% in the whole group. Analysis of risk factors at disease onset for TE identified positive lupus anticoagulant (p=0.17, RR=1.6), cryoglobulins (p<0.05, RR=1.8), and nephritis (p=0.05, RR=1.4), in addition to an age >40 at disease onset. CONCLUSIONS: A subgroup of patients in the Erlangen cohort with a typical clinical and serological phenotype at disease onset that is at high risk for a worse outcome was identified. Identification of these white patients at risk at disease onset will enable treatment to be intensified and thereby possibly prevent or better control late stage manifestations.

Fcgamma receptor IIa, IIIa, and IIIb polymorphisms in German patients with systemic lupus erythematosus: association with clinical symptoms.

BACKGROUND: Receptors for IgG play an important part in immune complex clearance. Several studies have identified polymorphisms of receptors for the Fc fragment of IgG (FcgammaR) as genetic factors influencing susceptibility to disease or disease course of systemic lupus erythematosus (SLE). OBJECTIVE: To examine these possibilities by evaluating a panel of clinical parameters in a cohort of 140 German patients with SLE for correlations with the FcgammaRIIa, IIIa, and IIIb polymorphisms in an explorative study. METHODS: 140 German patients with SLE according to American College of Rheumatology (ACR) criteria and 187 German controls were genotyped for the FcgammaRIIa, IIIa, and IIIb polymorphisms. Associations between FcgammaR genotypes, combined genotypes and clinical as well as laboratory features were analysed. RESULTS: No significant skewing of any of the three FcgammaR polymorphisms was seen in the German SLE cohort studied. Various clinical and serological parameters were found more frequently and at younger age in homozygous patients with the genotypes IIA-R/R131 or IIIA-F/F158 than in patients with IIA-H/H131 or IIIA-V/V158. These effects were even more pronounced in patients with the low binding combined phenotypes of the FcgammaRIIa, IIIa (double negative phenotypes) and FcgammaRIIa, IIIa, and IIIb (triple negative phenotypes). In patients with the double negative IIA and IIIA genotypes significantly higher frequencies of nephritis (63% v 33%) and proteinuria according to ACR criteria (58% v 11%), anaemia (84% v 55%), and anticardiolipin antibodies (63% v 22%) were found than in patients with the double positive genotypes. Patients with the IIA-R/R131 genotype and the double negative homozygous genotype had an earlier incidence of clinical symptoms, haematological and immunological abnormalities. Accordingly, SLE is diagnosed earlier in these patients, the difference reaching statistical significance only in the double negative v the double positive genotype (26.3 v 39.5 years) and the IIIA-F/F158 genotype v the rest (26.7 v 32.0 years). Most relevant is the fact that a higher median disease activity (ECLAM score) was demonstrated, both in the IIA-R/R131 homozygous (3.3 v 2.7) and the double negative (3.4 v 2.3) patients, reaching statistical significance in the first group. CONCLUSION: The results of this explorative study support the view that the FcgammaRIIa/IIIa and IIIb polymorphisms constitute factors influencing clinical manifestations and the disease course of SLE but do not represent genetic risk factors for the occurrence of SLE. Higher frequencies of clinical symptoms, haematological and immunological abnormalities as well as an earlier onset of clinical symptoms, haematological and immunological markers of active disease were found in patients with the IIA-R/R131 genotype and the double negative and triple negative genotypes.

Systemic lupus erythematosus. Disease outcome in patients with a disease duration of at least 10 years: second evaluation.

Data related to the disease course of patients with systemic lupus erythematosus (SLE) with special attention to the persistence of disease activity in the long term are scarce. At this moment reliable figures are only known about the survival rate as a measure of outcome. The aim of this multicenter study was to describe the outcome of SLE patients with a disease duration of greater than 10 y. Outcome parameters were two disease activity-scoring systems (SLEDAI and ECLAM), the end organ damage (SLICC/ACR damage index) and treatment. Our results are derived from 187 SLE patients followed at 10 different centres in Europe over a period of 1 y. Serious clinical signs or exacerbations, defined by the occurrence or detoriation of already existing symptoms of renal and cerebral nervous systems were observed in 2-11% of the patients, seizures and psychosis in 3%, proteinuria in 11% and an increase in serum creatinine in 5% of the patients. No change took place in the overall damage index. Yet, the disease course in most patients was characterized by periods of tiredness (42-60%), arthritis (20-25%), skin involvement such as malar rash (32-40%), migraine (15-20%), anaemia (15%) and leucopenia (17-19%). Summarizing these results it is shown that patients, still under care after such a long time of having this disease, do have a disease that is far from extinguished.

Incomplete lupus erythematosus: results of a multicentre study under the supervision of the EULAR Standing Committee on International Clinical Studies Including Therapeutic Trials (ESCISIT).

OBJECTIVE: Patients characterized with antinuclear antibodies (ANA) and disease symptoms related to one organ system can be described as having incomplete systemic lupus erythematosus (SLE). The aim of this multicentre study was to describe the outcome of these so-called incomplete SLE patients. Two aspects of the outcome were studied: (i) the disease course, defined by the presence or absence of clinical symptoms; and (ii) the number of patients that eventually developed full SLE. METHODS: Outcome parameters were the ACR criteria, the SLE disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measure (ECLAM) and the requirement for treatment. In 10 European rheumatology centres, patients who had been evaluated in the last 3 months of 1994 and had been diagnosed as having incomplete SLE on clinical grounds for at least 1 yr were included in the study. All 122 patients who were included in the study were evaluated annually during 3 yr of follow-up. RESULTS: Our results are confined to a patient cohort defined by disease duration of at least 1 yr, being under clinical care at the different centres in Europe. These patients showed disease activity that was related mostly to symptoms of the skin and the musculoskeletal system, and leucocytopenia. During the follow-up, low doses of prednisolone were still being prescribed in 43% of the patients. On recruitment to the study, 22 of the 122 incomplete SLE patients already fulfilled the ACR criteria for the diagnosis of SLE. In the 3 yr of follow-up only three patients developed SLE. CONCLUSIONS: A high proportion of patients in our cohort defined on clinical grounds as having incomplete SLE eventually showed disease activity defined by the SLEDAI as well as ECLAM. However, only three cases developed to SLE during the follow-up. This suggests that incomplete SLE forms a subgroup of SLE that has a good prognosis.

Systemic lupus erythematosus: clinical features in patients with a disease duration of over 10 years, first evaluation.

OBJECTIVE: Most information available about the disease course of patients with systemic lupus erythematosus (SLE) is restricted to the first 5 yr after disease onset. Data about the disease course 10 yr after disease onset are rare. The aim of this multicentre study was to describe the outcome of SLE patients with a disease duration of >10 yr. METHODS: Outcome parameters were the SLE Disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measure (ECLAM), the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SLICC/ACR), a global damage index (DI) and required treatment. In 10 different European rheumatology centres, all SLE patients who were evaluated in the last 3 months of 1994, and who had been diagnosed with SLE at least 10 yr ago, were included in the study. RESULTS: It should be stressed that our results are confined to a patient cohort, defined by a disease duration of at least 10 yr, and who are still under clinical care at the different centres in Europe. These SLE patients still showed some disease activity, related to symptoms of the skin and musculoskeletal systems, next to the presence of renal involvement. A total of 72% of the patients needed treatment with prednisolone (

Fcgamma receptor IIa polymorphism in Caucasian patients with systemic lupus erythematosus: association with clinical symptoms.

OBJECTIVE: The class II human leukocyte Fcy receptor for IgG (FcgammaRIIa) occurs in 2 codominantly expressed allelic forms (R131 and H131). Cells expressing IIa-H131 interact much more effectively with complexed IgG2 and IgG3 than do cells with IIa-R131. This might be linked to variability in immune complex handling, and therefore related to disease pathogenesis. The present study examines these possibilities in a cohort of Caucasian patients with systemic lupus erythematosus (SLE). METHODS: One hundred eight Caucasian patients were diagnosed with SLE according to the American College of Rheumatology criteria. The SLE patients and 187 Caucasian controls were genotyped for the FcgammaRIIa polymorphism, and associations between FcgammaRIIa genotypes, selected HLA haplotypes, and clinical as well as laboratory features were analyzed. RESULTS: No significant skewing of the FcgammaRIIa polymorphism was observed in the SLE cohort. Various clinical and serologic parameters were found more frequently or at a younger age in patients homozygous for the genotype IIa-R/R131 compared with those with the genotype IIa-H/H131. In patients with the genotype IIa-R/R131, significantly higher frequencies of proteinuria, hemolytic anemia, anti-nuclear RNP antibodies, and hypocomplementemia were found. The only clinical symptom observed more frequently in patients homozygous for IIa-H/H131 was livedo. Patients with the IIa-R/R131 genotype were significantly younger at disease onset and had an earlier incidence of arthritis, sicca syndrome, nephritis, lymphadenitis, hematologic abnormalities, immunologic abnormalities, lupus anticoagulant, cryoglobulinemia, and hypocomplementemia. HLA-DR3 was found in 41.7% of SLE patients, but was not associated with clinical symptoms, serologic abnormalities, or the homozygous genotypes of the FcgammaRIIa, although an association with a significantly later onset of SLE was found. CONCLUSION: The FcgammaRIIa polymorphism constitutes an additional factor that might influence the clinical manifestations and course of SLE, but does not represent a genetic risk factor for the occurrence of SLE.