[Current data on rheumatological care: annual report from the National database (NDB) of the regional collaborative arthritis centres in Germany]. / Aktuelle Zahlen zur rheumatologischen Versorgung ­ Jahresbericht aus der Kerndokumentation der regionalen kooperativen Rheumazentren.

In the National database (NDB) of the German regional collaborative arthritis centres, annual data on the rheumatological care of patients with inflammatory rheumatic diseases have been collected since 1993. This first annual report presents current cross-sectional data on medication and patient-reported outcomes gathered in 2022.

Association Between Rheumatoid Arthritis Disease Activity and Periodontitis Defined by Tooth Loss: Longitudinal and Cross-Sectional Data From Two Observational Studies.

OBJECTIVE: To analyze the effect of tooth loss/periodontitis on disease activity in early and established rheumatoid arthritis (RA). METHODS: Participants of the Course And Prognosis of Early Arthritis (CAPEA) early arthritis cohort reported their number of teeth at baseline. The number of teeth had been validated as a predictor of periodontitis. Clinical end points, including disease activity score (Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [ESR]), swollen joint count (SJC), ESR, and C-reactive protein level were collected at baseline, 3, 6, 12, 18, and 24 months. We used linear mixed regression models to estimate the association between tooth loss and clinical end points over time in early arthritis. For established RA, we analyzed cross-sectional data from the German National Database (NDB). All models accounted for age, sex, smoking, seropositivity, education level, and disease duration (only NDB). RESULTS: Among 1,124 CAPEA participants with early arthritis, those with higher tooth loss were older, more often male, smokers, and seropositive, and they had higher disease activity and inflammation markers at baseline. Tooth loss was associated with higher disease activity and ESR values over time. Inflammatory markers decreased comparably across tooth loss categories. Glucocorticoid use was higher among those with more tooth loss, whereas dose reduction was similar across tooth loss categories. Among 7,179 NDB participants with longstanding RA, disease activity and inflammation markers but not SJC were significantly higher in patients with more tooth loss. CONCLUSION: Although we observed an association between tooth loss and disease activity scores and inflammation markers in early and established RA, longitudinal results suggest that tooth loss does not hamper treatment response.

Identification of New, Functionally Relevant Mutations in the Coding Regions of the Human Fos and Jun Proto-Oncogenes in Rheumatoid Arthritis Synovial Tissue.

In rheumatoid arthritis (RA), the expression of many pro-destructive/pro-inflammatory proteins depends on the transcription factor AP-1. Therefore, our aim was to analyze the presence and functional relevance of mutations in the coding regions of the AP-1 subunits of the fos and jun family in peripheral blood (PB) and synovial membranes (SM) of RA and osteoarthritis patients (OA, disease control), as well as normal controls (NC). Using the non-isotopic RNAse cleavage assay, one known polymorphism (T252C: silent; rs1046117; present in RA, OA, and NC) and three novel germline mutations of the cfos gene were detected: (i) C361G/A367G: Gln121Glu/Ile123Val, denoted as "fos121/123"; present only in one OA sample; (ii) G374A: Arg125Lys, "fos125"; and (iii) C217A/G374A: Leu73Met/Arg125Lys, "fos73/125", the latter two exclusively present in RA. In addition, three novel somatic cjun mutations (604-606ΔCAG: ΔGln202, "jun202"; C706T: Pro236Ser, "jun236"; G750A: silent) were found exclusively in the RA SM. Tansgenic expression of fos125 and fos73/125 mutants in NIH-3T3 cells induced an activation of reporter constructs containing either the MMP-1 (matrix metalloproteinase) promoter (3- and 4-fold, respectively) or a pentameric AP-1 site (approximately 5-fold). Combined expression of these two cfos mutants with cjun wildtype or mutants (jun202, jun236) further enhanced reporter expression of the pentameric AP-1 construct. Finally, genotyping for the novel functionally relevant germline mutations in 298 RA, 288 OA, and 484 NC samples revealed no association with RA. Thus, functional cfos/cjun mutants may contribute to local joint inflammation/destruction in selected patients with RA by altering the transactivation capacity of AP-1 complexes.

Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study.

Our aim was to analyse (i) the presence of single nucleotide polymorphisms (SNPs) in the JUN and FOS core promoters in patients with rheumatoid arthritis (RA), knee-osteoarthritis (OA), and normal controls (NC); (ii) their functional influence on JUN/FOS transcription levels; and (iii) their associations with the occurrence of RA or knee-OA. JUN and FOS promoter SNPs were identified in an initial screening population using the Non-Isotopic RNase Cleavage Assay (NIRCA); their functional influence was analysed using reporter gene assays. Genotyping was done in RA (n = 298), knee-OA (n = 277), and NC (n = 484) samples. For replication, significant associations were validated in a Finnish cohort (OA: n = 72, NC: n = 548). Initially, two SNPs were detected in the JUN promoter and two additional SNPs in the FOS promoter in perfect linkage disequilibrium (LD). JUN promoter SNP rs4647009 caused significant downregulation of reporter gene expression, whereas reporter gene expression was significantly upregulated in the presence of the FOS promoter SNPs. The homozygous genotype of FOS promoter SNPs showed an association with the susceptibility for knee-OA (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.2⁻3.7, p = 0.0086). This association was successfully replicated in the Finnish Health 2000 study cohort (allelic OR 1.72, 95% CI 1.2⁻2.5, p = 0.006). FOS Promoter variants may represent relevant susceptibility markers for knee-OA.

Clinical presentation, burden of disease and treatment in young-onset and late-onset rheumatoid arthritis: a matched-pairs analysis taking age and disease duration into account.

OBJECTIVES: The aim of this study is to compare clinical features and treatment of young onset rheumatoid arthritis with late-onset rheumatoid arthritis. METHODS: Nine thousand five hundred forty-one patients with rheumatoid arthritis (RA) enrolled in the national database of the German Collaborative Arthritis Centres in 2007-2009 were stratified by age at disease onset: up to 65 years (YORA), >65 years (LORA). To enable unbiased comparisons between the two groups despite their systematic differences in age and disease duration, we performed two separate matched-pairs analyses: the impact of current age was assessed by matching YORA and LORA patients for disease duration and sex (n=1,550 pairs). To identify the influence of disease duration, a second sample matched for age and sex (n=1,158 pairs) was drawn. RESULTS: At identical age, YORA patients had higher disease activity (DAS28), worse functional capacity and were less frequently in remission when compared with LORA patients. YORA patients also suffered more frequently from RA-related co-morbidities such as cardiovascular disease, chronic renal disease and osteoporosis. Matched for disease duration, there were no differences between the two groups concerning disease severity and remission rates, global health or pain intensity. Independent of age or disease duration, YORA patients reported more sleep disorders and fatigue. LORA patients received significantly fewer synthetic or biologic DMARDs than YORA patients. CONCLUSIONS: Duration of RA, rather than age, explains differences in disease burden between YORA and LORA patients. The lower prescription rates of synthetic and in particular biologic DMARDs, despite lower remission rates, indicate a potential treatment deficit in older patients.

The balance between soluble receptors regulating IL-6 trans-signaling is predictive for the RANKL/osteoprotegerin ratio in postmenopausal women with rheumatoid arthritis.

The objective of this study is to investigate the relationship between soluble components of the interleukin 6 (IL-6) system mediating and modifying IL-6 trans-signaling and the RANKL-RANK-osteoprotegerin system in postmenopausal women with rheumatoid arthritis (RA). The following parameters were investigated in 126 postmenopausal women with RA: IL-6, soluble IL-6-receptor (sIL-6R), soluble glycoprotein 130 (sgp130), sRANKL, osteoprotegerin (OPG), osteocalcin, erythrocyte sedimentation rate and C-reactive protein in sera, pyridinolin and desoxypyridinolin crosslinks in the morning urine. Bone mineral density (BMD) was measured by dual X-ray absorptiometry at the lumbar spine (BMD-LS) and at the femoral neck (BMD-FN). Predictors of RANKL/OPG ratio and BMD were evaluated by multiple linear regression analysis. The following determinants of the RANKL/OPG ratio were identified: sIL-6R/sgp130 ratio and daily glucocorticoid (GC) dose as positive determinants in the whole group (R (2) = 0.56; P = 0.001), sIL-6R/sgp130 ratio as the exclusive positive determinant in patients with GC therapy (R (2) = 0.48; P = 0.001) and sgp130 as negative determinant in patients without GC (R (2) = 0.42; P = 0.031). Sgp130 was highly significantly positively correlated with OPG in the whole group (P < 0.001) as well as in patients with (n = 70; P < 0.05) and without GC therapy (n = 56; P < 0.01). sIL-6R was the main negative predictor of BMD-LS (R (2) = 0.41; P = 0.019). High sIL-6R/sgp130 ratio and/or low sgp130 are associated with a high sRANKL/OPG ratio in sera of postmenopausal women with RA indicating the critical significance of IL-6 trans-signaling for an increase in the RANKL/OPG ratio and of bone resorption. Inhibition of IL-6 trans-signaling may be an effective bone-protecting principle in postmenopausal women with RA.

Influence of Rituximab on markers of bone remodeling in patients with rheumatoid arthritis: a prospective open-label pilot study.

Immune system and bone are interacting in a complex way. Rheumatoid arthritis is characterized not only by joint destruction, but also by development of systemic osteopenia and osteoporosis. The CD20-depleting antibody Rituximab (Rtx) is a novel therapeutic option able significantly to slow the destructive joint process of rheumatoid arthritis. However, there are little data whether Rtx influences systemic bone remodeling. In the present prospective study, we evaluated the influence of Rtx on markers of bone metabolism with a follow-up of 3-15 months after Rtx therapy (2 dose of each 1,000 mg) in 13 patients with rheumatoid arthritis. There was no significant change of the bone formation markers bone alkaline phosphatase and c-terminal propeptide of collagen I. However, a non-significant tendency of decrease of RANKL (with no chance of osteoprotegerin) and a significant decrease of the bone degradation marker desoxypyridinolin crosslinked collagen I was observed 15 months after Rtx application. These initial results provide no evidence of a negative systemic influence of Rtx on bone remodeling. In contrast, it appears that Rtx lowered osteoclast activity often found increased in active rheumatoid arthritis contributing to osteoporosis in this disease.

Implementation of Z-scores as an age- and sex-independent parameter for estimating joint space widths in rheumatoid arthritis.

OBJECTIVE: To compare normative data of joint space distances (JSD) with the JSD of patients with rheumatoid arthritis (RA) as measured by computer-aided joint space analysis (CAJSA) at the metacarpophalangeal (MCP) articulations, and to differentiate age- and sex-related alterations from the disease-related joint space narrowing. METHODS: In total, 256 healthy subjects and 248 patients with verified RA (following revised ACR criteria) underwent computerized semiautomated measurements of JSD (CAJSA, version 1.3.6) at the MCP articulation (JSD-MCP) based on digital radiographs. The Z-score, a comparative parameter that differentiates joint space alterations caused by RA-related cartilage destruction from age- and sex-related changes, was calculated. RESULTS: Our data showed a relationship between measured joint space widths (MCP total and MCP thumb to little finger) and age for healthy subjects and also the RA group. The RA group revealed an age-related joint space narrowing that was surpassed by the RA-related narrowing of joint space widths classified by Sharp joint space narrowing score and resulting in smaller Z-scores for RA patients. CONCLUSION: The CAJSA technique seems to distinguish age-related JSD changes in healthy volunteers from RA-induced alterations. In addition the Z-score was also able to differentiate RA-dependent narrowing of JSD. Calculation of the Z-scores based on sex- and age-specific reference data may facilitate earlier identification of patients with RA, allowing initiation of a more optimal, individually adapted therapeutic strategy.

Long-term moderate intervention with n-3 long-chain PUFA-supplemented dairy products: effects on pathophysiological biomarkers in patients with rheumatoid arthritis.

n-3 long-chain PUFA (n-3 LC-PUFA) may improve cardiovascular and inflammatory diseases. The effects of n-3 LC-PUFA-supplemented dairy products on inflammation and immunological parameters, biomarkers of oxidative stress, serum lipids, and on disease activity were determined in patients with rheumatoid arthritis (RA). Forty-five subjects (forty-three females and two males) were randomly divided into two groups in a double-blind, placebo-controlled cross-over study. Both groups received placebo or verum products consecutively for 3 months with a 2-month washout phase between the two periods. Blood samples were taken at the beginning and at the end of each period. The dairy products generally improved serum lipids by increasing HDL and lowering lipoprotein a. The n-3 LC-PUFA supplements act to lower TAG. Additionally, a decreased lipopolysaccharide-stimulated cylo-oxygenase-2 expression was found in patients who had consumed the enriched dairy products. The majority of the CD analysed were not influenced, although n-3 LC-PUFA did suppress the immune response as lymphocytes and monocytes were found to be significantly decreased. The n-3 LC-PUFA did not increase the biomarkers of oxidative stress such as 8-iso-PGF(2alpha) and 15-keto-dihydro PGF(2alpha), and DNA damage like 7,8-dihydro-8-oxo-2'-deoxyguanosine. The long-term consumption of dairy products (2 x 12 weeks) diminished the excretion of hydroxypyridinium crosslinks, and favoured the diastolic blood pressure. The consumption of moderate doses of n-3 LC-PUFA in combination with dairy products did not improve the disease activity. However, there is evidence of cardioprotective effects. Furthermore, the long-term consumption of dairy products acts against the cartilage and bone destruction in RA.

Impact of sex, age, body mass index and handedness on finger joint space width in patients with prolonged rheumatoid arthritis using computer-aided joint space analysis.

To evaluate the associations between sex, age, body mass index (BMI) and handedness regarding the radiogeometric detectable joint space distances of the finger articulations in patients suffering from a prolonged course of rheumatoid arthritis (RA). The joint space widths were measured by a new available Computer-aided joint space analysis (CAJSA); 128 patients with RA underwent computerized semi-automated joint space analysis of joint space distances at the metacarpal-phalangeal articulation (JSD-MCP II-V), proximal-interphalangeal joint (JSD-PIP II-V) and distal-interphalangeal joint (JSD-DIP II-V) based on digitally performed radiographs of the hand (Radiogrammetry Kit, Version 1.3.6; Sectra; Sweden). The joint space distance (JSD) of each articulation was expressed as JSD total in millimeter. The patient cohort was differentiated for gender, age, handedness and BMI (BMI < 20; BMI 20-25, BMI > 25). JSD revealed a significant age-related narrowing of 24.8% (JSD-MCP), 22.6% (JSD-PIP) and 28.7% (JSD-DIP) between the ages of 20 and 79. Additionally, males showed a significantly wider JSD compared to the female cohort for all age groups. All JSD-distances were varied between the right and left hand. The JSD-MCP demonstrated significant differences regarding the BMI groups. In contrast to JSD-MCP an effect of the BMI on measurements of JSD-PIP and JSD-DIP could not be observed. These influences must be differentiated from disease-related alterations caused by RA.

Effects of leflunomide and methotrexate in rheumatoid arthritis detected by digital X-ray radiogrammetry and computer-aided joint space analysis.

The aim of the present study was to evaluate the effect of long-term leflunomide and methotrexate (MTX) therapy during the course of rheumatoid arthritis (RA) estimated by digital X-ray radiogrammetry (DXR) and computer-aided joint space analysis (CAJSA) as diagnostic tools for the quantification of disease-related periarticular osteoporosis and joint space narrowing. Fourty matchable patients with verified RA were treated with leflunomide or MTX during an observation period of 2.5 years. All patients underwent complete computerized calculations of bone mineral density (BMD) and metacarpal index (MCI) by DXR as well as semi-automated measurements of joint space widths (JSW) at the metacarpophalangeal articulations (MCP, thumb to small finger) and proximal interphalangeal joints (PIP, index finger to small finger) using digitized hand radiographs. DXR-BMD revealed an increase of 0.4% (leflunomide-group) versus a reduction of -9.1% (MTX-group). Regarding DXR-MCI, a reduction of -1.1% (leflunomide-group) and -5.3% (MTX-group) was observed. The CAJSA parameters showed a decline of -2.7% (JSW-MCP) versus -2.1% (JSW-PIP) in patients treated with leflunomide. An accentuated joint space narrowing was revealed (JSW-MCP: -5.7%; JSW-PIP: -6.2%) in the MTX group. Digital X-ray radiogrammetry and CAJSA could discriminate the influence of different therapeutic regimes on periarticular osteoporosis and joint space narrowing showing a less accentuated radiographic progression in patients treated with leflunomide.

Increased frequency of EBV-specific effector memory CD8+ T cells correlates with higher viral load in rheumatoid arthritis.

EBV is a candidate trigger of rheumatoid arthritis (RA). We determined both EBV-specific T cell and B cell responses and cell-associated EBV DNA copies in patients with RA and demographically matched healthy virus carriers. Patients with RA showed increased and broadened IgG responses to lytic and latent EBV-encoded Ags and 7-fold higher levels of EBV copy numbers in circulating blood cells. Additionally, patients with RA exhibited substantial expansions of CD8(+) T cells specific for pooled EBV Ags expressed during both B cell transformation and productive viral replication and the frequency of CD8(+) T cells specific for these Ags correlated with cellular EBV copy numbers. In contrast, CD4(+) T cell responses to EBV and T cell responses to human CMV Ags were unchanged, altogether arguing against a defective control of latent EBV infection in RA. Our data show that the regulation of EBV infection is perturbed in RA and suggest that increased EBV-specific effector T cell and Ab responses are driven by an elevated EBV load in RA.

Significance of risk factors for osteoporosis is dependent on gender and menopause in rheumatoid arthritis.

The aim of our study was to compare the significance of risk factors for osteoporosis according to gender and menopausal state in patients with rheumatoid arthritis (RA). Bone mineral density (dual X-ray absorptiometry), cumulative glucocorticoid dose, age, disease duration, body mass index (BMI) and parameters of disease activity and bone turnover were registered in 343 postmenopausal women, 100 premenopausal women and 108 men with RA. Osteoporosis was found in a significantly higher percentage in postmenopausal women (55.7%) and in men (50.5%) in comparison with premenopausal women (18%; P < 0.001). The following risk factors for osteoporosis were found: older age, low BMI and high cumulative glucocorticoid dose in postmenopausal women, low BMI and high cumulative glucocorticoid dose in men and low BMI in premenopausal women. There is a very high prevalence of osteoporosis not only in postmenopausal women but also in men with RA. Osteoporosis risk factors are strongly dependent from gender and menopausal state.

Computer-aided joint space analysis (CAJSA) of the proximal-interphalangeal joint-normative age-related and gender specific data.

RATIONALE AND OBJECTIVES: To provide reference data for computer-aided joint space analysis (CAJSA) based on a semiautomated and computer-aided diagnostic system for the measurement of joint space widths (ie, proximal-interphalangeal joint), considering gender-specific and age-related differences. MATERIALS AND METHODS: A total of 869 subjects were enrolled (351 females/518 males) with radiographs of the hand. All participants underwent measurements of joint space distances at the proximal-interphalangeal articulation (JSD-PIP) of the second to fifth finger using CAJSA technology. RESULTS: The data verify a notable age-related decrease of CAJSA parameters, showing an accentuated age-related joint space narrowing in women. Additionally, males showed a significant wider JSD-PIP (+15.4%) compared with the female cohort for all age groups. CONCLUSIONS: Our data present gender-specific and age-related normative reference values for computer-aided joint space analysis of JSD-PIP and provide a valid and reliable quantification of disease-related joint space narrowing, particularly in patients with osteoarthritis and rheumatoid arthritis involving the peripheral small hand joints.

Hypercalcemia in rheumatoid arthritis: relationship with disease activity and bone metabolism.

To investigate the relationship between ionized calcium and disease activity, parameters of bone metabolism and bone mineral density (BMD) at the lumbar spine (BMD-LS) and the femoral neck (BMD-FN) measured by dual X-ray absorptiometry in rheumatoid arthritis (RA). In 146 patients with RA, the following parameters were investigated: serum levels of ionized calcium, total calcium, vitamin D metabolites 25-hydroxyvitamin D3 (25D3) and 1,25-dihydroxyvitamin D3 (1,25D3), intact parathyroid hormone (iPTH), interleukin-6, osteocalcin, erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP); renal excretion of pyridinolin (PYD)- and desoxypyridinolin (DPD)-crosslinks. A total of 30.1% of the patients were hypercalcemic (ionized calcium >1.30 mmol/l). In comparison with normocalcemic patients, those with hypercalcemia had significantly higher ESR (P<0.01) and CRP values (P<0.05) and significantly lower serum levels of both iPTH (P<0.01) and 1,25D3 (P<0.05) and a significantly lower BMD-LS (P<0.05). The results indicate that a substantial part of RA patients is hypercalcemic. Hypercalcemia is associated with high disease activity and may contribute to suppression of PTH secretion and vitamin D hormone synthesis. High levels of ionized calcium may be a reflection of disease-activity-related systemic bone loss, and could be a predictor of BMD at the lumbar spine in RA.

Cytokines, osteoprotegerin, and RANKL in vitro and histomorphometric indices of bone turnover in patients with different bone diseases.

Cytokines are supposed to play an essential role in the regulation of the bone metabolic unit. However, information on cytokine production of primary human osteoblasts from patients with metabolic bone disease is scarce, and few attempts have been made to correlate such data to histomorphometric parameters of individual patients. We investigated 11 patients with metabolic bone disease referred to our outpatient department for bone biopsy and analyzed interleukin (IL)-1, IL-6, and TNF-alpha protein release and gene expression in primary osteoblast cultures. Compared with four controls, five patients showed normal cytokine protein release, whereas six patients showed much higher levels of interleukin-6 (26-fold) and TNF-alpha (84-fold). All three cytokines were strongly correlated concerning gene expression and/or protein levels (r = 0.72-0.96). Histomorphometric analysis of the bone samples showed that eroded surface (ES/BS) as a parameter of bone resorption was significantly associated with TNF-a. In addition, RANKL gene expression was positively associated with ES/BS and osteoclast surface (Oc.S/BS). Finally, the formation parameters osteoid volume and osteoid surface were negatively associated with TNF-alpha. In conclusion, in an in vitro-ex vivo model of bone cells obtained from a group of 11 patients with different forms of metabolic bone disease, cytokine release in conditioned medium was significantly associated with bone resorption and bone formation, as quantified by histomorphometry. TNF-alpha seemed to be the more important cytokine; its effect on bone resorption could be mediated by RANKL.