[Glucocorticoid-induced osteoporosis-Focus treatment (part 1)]. / Glukokortikoid-induzierte Osteoporose ­ Fokus Therapie (Teil 1).

With a fracture prevalence of 30-50%, glucocorticoid (GC)-induced osteoporosis is one of the most important comorbidities in inflammatory rheumatic diseases. Because of a reduction of bone quality with a lack of correlation with bone mineral density, the fracture risk during long-term GC treatment is not sufficiently represented by the currently available methods of osteodensitometry and therefore underestimated. According to the Confederation for Osteology (DVO) guidelines, a baseline osteological diagnosis including osteodensitometry is indicated in all postmenopausal women and in men aged 60 years and older who receive or are scheduled to receive GC at a dose of ≥ 2.5 mg prednisolone equivalent/day for > 3 months. Basic measures in GC-treated patients include vitamin D and calcium supplementation as well as measures to promote muscle strength and coordination and to prevent falls. The indications for a specific osteological treatment depend on the calculated GC dose, age, sex, and other fracture risk factors in addition to bone mineral density and prevalent fractures.

[Glucocorticoid-induced osteoporosis-Focus treatment (part 2)]. / Glukokortikoid-induzierte Osteoporose ­ Fokus Therapie (Teil 2).

The following substances are approved for the treatment of glucocorticoid-induced osteoporosis: the oral bisphosphonates alendronate and risedronate, the intravenous bisphosphonate zoledronate, the RANKL antibody denosumab as antiresorptive substances and teriparatide as osteoanabolic substance. In comparison to placebo a reduction of vertebral fractures is proven for all mentioned substances. Thereby, teriparatide is more effective than alendronate and risedronate with respect to the reduction of vertebral fractures. The severity of osteoporosis, especially the presence of osteoporotic fractures, the approach of treatment (preventive or curative) and contraindications are factors that are important for the differentiated application of the mentioned substances. Furthermore, it must be noted that the effect of osteoanabolic treatment must be stabilized by a subsequent antiresorptive treatment and that after termination of antiresorptive treatment with denosumab a temporary bisphosphonate treatment is required to prevent a rebound phenomenon.

[Which patients with rheumatoid arthritis do not receive DMARD treatment? Analysis of data from the German Collaborative Arthritis Centers]. / Welche Patienten mit rheumatoider Arthritis erhalten keine DMARD-Therapie? Eine Analyse von Daten der Kerndokumentation.

BACKGROUND: The vast majority of patients with rheumatoid arthritis (RA) included in the national database of the German Collaborative Arthritis Centers are treated with disease-modifying antirheumatic drugs (DMARD). The clinical and patient-related characteristics of patients who did not have DMARD treatment in the longer term were investigated. METHODOLOGY: Between 2012 and 2016 a total of 10,289 patients with RA were documented. Patient characteristics, disease activity and severity, comorbidities and concomitant treatment were descriptively evaluated. Patients who were without DMARDs for more than 1 year and not in remission (disease activity score 28, simple disease activity index or Boolean remission) were analyzed separately. Logistic regression was used to investigate which variables were associated with DMARD treatment. RESULTS: A total of 426 patients were ≤1 year without DMARDs, 1090 > 1 year without DMARDs and 8773 (85%) currently had DMARD treatment. Of the patients who were without DMARDs for more than 1 year, 51% were in remission. Even if no remission criteria were met, the rheumatologists nevertheless found the strived for RA situation in the majority of patients. Of the patients who were without DMARDs for more than 1 year, 13% received glucocorticoid treatment >5 mg/day. In patients with a high degree of severity (odds ratio, OR severe vs. asymptomatic/mild 2.33, 95% confidence interval, CI 1.80;3.02) or positive rheumatoid factor (OR 2.24, CI 1.96;2.56) the chance of receiving DMARD treatment was twice as high. Existing comorbidities did not reduce the chance of receiving DMARD treatment. CONCLUSION: The RA patients in the national database who had no DMARDs for more than 1 year were mostly in remission or with low disease activity. Signs of inadequate disease control were found in only 11% of all patients without DMARD treatment.

[Medical treatment of rheumatoid arthritis in 2014 : Current data from the German Collaborative Arthritis Centers]. / Versorgung der rheumatoiden Arthritis 2014 : Aktuelle Daten aus der Kerndokumentation.

BACKGROUND: Since the introduction of biologic treatment in rheumatoid arthritis (RA), disease activity and treatment modalities have changed substantially. The current provision and developments in recent years are analyzed with annual data from the National Database of the Collaborative Arthritis Centers in Germany. METHODS: To analyze disease activity, diagnostics and treatment in RA patients in 2014 with regard to seropositivity and disease duration. Time trends from 2007-2014 are reported for disease activity (DAS28) distribution and biologic treatment. RESULTS: In 2014, a total of 8,084 RA patients were analyzed: 72 % were rheumatoid factor and/or ACPA positive, the mean age was 62 years and the mean disease duration 12 years. According to DAS28, 35.9 % were in remission, 19.2 % had low, 37.1 % moderate and 7.8 % high disease activity. An increase since 2007 was only observed in patients with a disease duration >2 years. Synthetic DMARDS were used for treatment in 78 %. Biologic treatment increased from 16 % (2007) to 27 % (2014). Especially those patients with a disease duration >5 years were treated more frequently with biologics. Seronegative patients had slightly less severe mean disease activity parameters. They were treated equally frequent with DMARDS but only half as often with biologics compared to seropositive patients. CONCLUSION: The use of biologics in RA patients has increased since 2007; however this was not observed in patients with short disease duration. Early intensive treatment adaption seems justified to improve disease activity in the large portion of patients who do not reach low disease activity under conventional DMARDs.

Decreased RAGE expression in peripheral blood mononuclear cells of patients with rheumatoid arthritis.

OBJECTIVE: Interactions between the multiligand receptor for advanced glycation end products (RAGE) and its proinflammatory ligands (AGEs, S100/calgranulins, HMBG1, Mac-1) may contribute to inflammatory responses playing a key role in the pathogenesis of chronic inflammatory diseases such as in rheumatoid arthritis (RA). Peripheral blood mononuclear cells (PBMCs) participate in the development of chronic inflammatory diseases. This study investigated expression of the RAGE variants endogenous secretory RAGE (esRAGE), N-truncated RAGE (NtRAGE) and complete RAGE (cRAGE: encoding full-length RAGE, esRAGE and NtRAGE) in PBMCs of patients with RA in comparison to healthy control subjects (controls) and to patients with Crohn's disease (CD) as another chronic inflammatory disease. METHODS: The cRAGE, esRAGE and NtRAGE mRNA expression levels of PBMCs from controls, RA and CD patients were measured by real-time PCR. The RAGE protein expression was determined by Western blot analysis and the esRAGE plasma levels by ELISA. RESULTS: PBMCs of RA patients showed significantly decreased mRNA expression for cRAGE (46%), esRAGE (54.0%) and NtRAGE (52%) in comparison to healthy controls (100%). For CD patients, also a down-regulation but to a lower extent was found (cRAGE: 79%; esRAGE: 76%; NtRAGE: 69%). Related to controls, RA PBMCs showed a significantly reduced protein expression of full-length RAGE (53%) as well as significantly decreased esRAGE plasma concentrations (70%). CONCLUSION: The down-regulation of RAGE isoforms in RA PBMCs may contribute to reduced intracellular responses mediated by the cell-standing receptor as well as to a lowered capability of trapping inflammatory ligands by circulating esRAGE.

Soluble receptor activator of NFkappa B-ligand and osteoprotegerin in rheumatoid arthritis - relationship with bone mineral density, disease activity and bone turnover.

The aim of our study was to investigate determinants of bone mineral density (BMD) measured by dual X-ray absorptiometry at the lumbar spine (BMD-LS) and at the femoral neck (BMD-FN) in patients with rheumatoid arthritis (RA) with special respect to bone resorbing proinflammatory cytokines and their physiological antagonists. In 142 RA patients the following parameters were measured in parallel with BMD: serum levels of soluble receptor activator of nuclear factor kappa-B-ligand (sRANKL), osteoprotegerin (OPG), interleukin (IL)-6, soluble glycoprotein 130 (sgp130), 25-hydroxyvitamin D3 (25OHD(3)), 1,25-dihydroxyvitamin D3 (1,25[OH](2)D(3)), intact parathyroid hormone, osteocalcin, ionized calcium, renal excretion of pyridinolin and deoxypyridinolin, C-reactive protein, and erythrocyte sedimentation rate (ESR). No significant differences of sRANKL, OPG, IL-6, and spg130 were found between patients with osteoporosis (47.9% of patients), osteopenia (36.6%), and normal BMD (15.5%). However, total sRANKL was significantly higher in postmenopausal women with osteoporosis at FN than in those without (p < 0.05) and showed a negative correlation with BMD-LS in patients older than 60 years (p = 0.01). BMD-LS and BMD-FN (p < 0.001) and total sRANKL (p < 0.01) were negatively related with the age of the patients. Only IL-6 (positive correlation, p < 0.001) and 1,25(OH)(2)D(3) (negative correlation, p < 0.001) but not sRANKL, OPG, and sgp130 were related to disease activity. Using multiple linear regression analysis, menopause was identified as the crucial negative determinant of BMD-LS (R (2) = 0.94, p = 0.001), whereas cumulative glucocorticoid dose (beta = -0.80, p = 0.001) and ESR (beta = -0.44, p = 0.016) were the negative determinants of BMD-FN (R (2) = 0.86, p = 0.001). The results indicate that influences of age and gender must be considered in investigations on the relationship between BMD and sRANKL in RA and that high serum levels of sRANKL seems to be associated with osteoporosis only in subgroups of RA patients.

Factors modifying collagen catabolism in patients with ankylosing spondylitis.

OBJECTIVE: We quantified the total excretion of the collagen crosslinks (CL) pyridinoline (PYD) and deoxypyridinoline (DPD) in 108 ankylosing spondylitis (AS) patients (29 f, 79 m) in correlation to different characteristics of disease to evaluate different mechanism contributing to development of osteoporosis in AS. METHODS: PYD and DPD were measured by HPLC. RESULTS: AS patients show a highly significant positive correlation between PYD and inflammatory activity. In cases involving peripheral joints, significantly higher CL levels in urine were found. Patients with syndesmophytes excreted significantly more CL vs. those without. In the more advanced stages of sacroiliitis (stage III and IV), CL levels tended to be higher. Among those patients treated with NSAIDs, a tendency to decreased levels of DPD and consecutive raised levels of the quotient PYD/DPD were observed. No significant correlation was found between restricted spine mobility or duration of disease and amount of excreted CL. CONCLUSIONS: Our investigations show that the inflammatory process, the involvement of the peripheral joints, the presence of syndesmophytes and the stage of sacroiliitis all have an influence on the extent of collagen degradation in AS patients. NSAIDs do not increase but appear to reduce collagen I catabolism.

Clinical manifestation of POEMS syndrome with features of connective tissue disease.

The POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome is a rare plasma cell disease with multiorgan involvement and varying clinical manifestations. We report a 38-year-old man who presented with scleroderma-like skin changes of the hands and feet, sicca and Raynaud's syndrome, pleural effusions, glomerulopathy, polyneuropathy, hepatosplenomegaly and lymphadenopathy. Steroid treatment was started on the assumption of a connective tissue disease and led to a temporary improvement. During the further course of the disease, hypothyreosis, monoclonal gammopathy and osteosclerotic bone lesions were detected, leading to the diagnosis of POEMS syndrome. This case emphasises the need to consider POEMS syndrome as a differential diagnosis in patients with signs of connective tissue disease and polyneuropathy.

The determination of pyridinium crosslinks in urine and serum as a possible marker of cartilage degradation in rheumatoid arthritis.

The determination of the collagen crosslinks pyridinoline (Pyd) and deoxypyridinoline (Dpyd) seems to be a successful way of characterizing topic destructive processes in rheumatoid arthritis (RA). Dpyd is a specific marker of collagen I resorption in bone, whereas Pyd is released from types I and II collagen in bone and cartilage. Both crosslinks were examined in 38 RA patients concurrently by RP-gradient-HPLC in urine and serum. A positive correlation was found between the inflammatory activity (measured by CrP) and the level of collagen crosslinks in urine. A correlation between serum and urine concentrations was demonstrable for Pyd, but not for Dpyd. Different elimination kinetics for fragments containing either Pyd or Dpyd are a possible explanation for this observation. The ratio of Pyd/Dpyd is known to be a useful marker to distinguish between destruction of cartilage and bone collagen. Because the Pyd/Dpyd ratio in urine does not necessarily correspond to that in serum, probably as a result of metabolic or elimination processes, the usefulness of the relationship between the crosslinks in urine as a method of differentiating between cartilage and bone degradation must be questioned.

Influence of methotrexate and azathioprine on radiologic progression in rheumatoid arthritis.

We investigated 43 patients with seropositive rheumatoid arthritis (RA) under a therapy with methotrexate (MTX) or azathioprine (AZA). All patients fulfilled the American Rheumatism Association criteria. It has been a retrospective study over 2.6 years (MTX: 26 patients, average age 54 +/- 14.6 years, female/male 19:7, AZA: 17 patients, average age 59.4 +/- 12.5 years, female/male 12:5). The mean duration of disease was 8 years (+/- 5.3) in the MTX-group and 7 years (+/- 7.3) in the AZA-group. The mean dose of MTX was 13. 3mg/week and of azathioprine 142.6mg/ daily. The drugs were administered orally. - Radiographs of hands, wrists and feet obtained at enrollment and at review were scored by a rheumatologist according to a modified Larsen score. Radiographic damages were counted in 25 joints of each hand and in 25 joints of each foot. The change in radiological score was calculated by subtracting the joint damage scores at follow up with first damage score at inclusion. The rate of radiological progression (YP) was calculated by dividing the change in radiological score by the number of years during the period of study. - Only 3 patients with MTX showed no radiologic progression. All other patients of both groups showed progressive radiological changes. - The study demonstrated no significant difference in the rate of radiologic progression between the different treatment-groups. However, there was a trend that MTX treated patients (YP 5 +/- 4.4) had a slower radiographic progression compared with those treated with AZA (YP 8.5 +/- 7.7). MTX may be more effective in patients at an earlier stage of rheumatoid arthritis. - When we started a therapy with AZA or MTX in a later period of disease we revealed a better influence of radiologic progression under AZA and a trend towards an increase of the radiologic progression under MTX. - Probably there is a decreasing effect of MTX in later periods of the disease. - The corticoid dose reduction was higher under AZA (AZA: Reduction about 58.6%, MTX: 25%) over the study duration. - Our investigation demonstrated a trend towards reduced radiological progression in MTX treated patients compared to AZA, however statistic analysis showed no significant difference in the rate of radiologic progression. At an earlier stage of the disease there is a better influence of MTX in radiologic progression, at the later stage we showed a slowing of radiological deterioration in AZA treated group.

[Diarrhea as the initial manifestation of medullary thyroid gland carcinoma]. / Diarrhö als Erstmanifestation eines medullären Schilddrüsenkarzinoms.

BACKGROUND: With the differential diagnosis of a diarrhea a lot of causes has to be considered. In very rare cases diarrhea can be the first symptom of a medullary thyroid carcinoma (MTC). CASE REPORT: A 28-year-old patient came to the admission department because of persisting diarrhea. A computerized tomography revealed multiple hepatic and pulmonary metastases. A medullary thyreoid carcinoma was found as the cause of it. The serum calcitonin values were highly increased, later the carcinoembryonal antigen (CEA), too. Sandostatin, a radioimmune therapy (131J-anti-CEA antibody) and adriamycin were therapeutically applied. The patient died 24 months after the occurrence of the first symptoms. CONCLUSION: In case of persisting diarrhea the differential diagnosis of a medullary thyroid carcinoma must be taken into consideration and a calcitonin determination has to be arranged. Yet, typical symptoms like struma nodosa, swollen neck lymph nodes or a CEA increase can still be missing in the initial phase.

[Is the guideline, "Management of early rheumatoid arthritis," being followed in a rheumatism center?]. / Wird die Leitlinie "Management der frühen rheumatoiden Arthritis" an einem Rheumazentrum umgesetzt?

BACKGROUND: There are indications that the influence of external guidelines on the quality of health care is limited and they are little or not at all used in clinical practice. It was the aim of this study to examine how and to what extent the external S3 guideline "Management of Early Rheumatoid Arthritis" was applied in a rheumatism center. MATERIALS AND METHODS: In accordance with the data of all rheumatoid arthritis patients, who were treated November 2007, an investigation was carried out on the degree of application and realization of the S3 guideline which had been changed into an internal guideline. The primary objective was the Disease Modifying Anti-Rheumatic Drug (DMARD) therapy; secondary objectives were the administration of methotrexate with folic acid, the administration of glucocorticoids with calcium and vitamin D; and NSAR monotherapy. RESULTS: 94.6 % of the patients were given a therapy of basis drugs (DMARDs). 82.5 % of the methotrexate patients additionally received folic acid. 65.9 % of the patients received, in addition to glucocorticoids, calcium and vitamin D. In 99.1 % of the cases NSAR monotherapy was instituted. CONCLUSION: The high degree of application does not correspond with the results of previous studies on guideline compliance with external guidelines. A possible explanation of this may be the change made of the external guideline to a guideline within the hospital.

Peripheral bone status in rheumatoid arthritis evaluated by digital X-ray radiogrammetry and compared with multisite quantitative ultrasound.

The development of secondary osteoporosis in rheumatoid arthritis (RA) has recently become well recognized, characterized by demineralization at axial and in particular periarticular peripheral bone sites. Our aim was to evaluate multisite quantitative ultrasound (QUS) compared to digital X-ray radiogrammetry (DXR) by the quantification of cortical bone loss dependent on the severity of RA. Fifty-three patients with verified RA underwent QUS measurements (Sunlight Omnisense 7000) with estimation of the speed of sound (QUS-SOS) at the distal radius and at the phalanx of the third digit. Also, bone mineral density (DXR-BMD) and metacarpal index (DXR-MCI) were estimated on metacarpals II-IV using DXR technology. Additionally, Larsen score and Steinbroker stage were assessed. Disease activity of RA was estimated by disease activity score 28 (DAS 28). For the group with minor disease activity (3.2 5.1), QUS-SOS of the radius revealed a significant correlation to DXR-BMD (R = 0.71) and DXR-MCI (R = 0.84), whereas for QUS-SOS (phalanx) no significant association to the DXR parameters was shown. The DXR parameters and, to a lesser extent, the QUS data also demonstrated pronounced declines in the case of accentuated disease activity (DAS > 5.1). Both DXR-BMD (-25.9 %, P < 0.01) and DXR-MCI (-38.6 %, P < 0.01) revealed a notable reduction dependent on the severity of RA. Otherwise, QUS-SOS marginally decreased, with -2.6% (radius) and -3.9% (phalanx). DXR revealed a significant reduction of DXR-BMD as well as DXR-MCI dependent on the severity of RA and surpassed multisite QUS as a promising diagnostic tool.

[Rheumatoid factor activity, age at manifestation and roentgenologic progression of rheumatoid arthritis--a retrospective study]. / Rheumafaktoraktivität, Manifestationsalter und röntgenologische Progredienz der rheumatoiden Arthritis (RA)--eine retrospektive Studie.

The outcome of RF-activity (measured by hemagglutination in the modification of Podliachouk-Harboe) was investigated in 95 patients with RA. In 52 of these patients the radiological progression (modification of Larsen index for hands and feet) in correlation to the outcome of RF was assessed. The results can be summarized in the following way: 1. Elderly RA patients show a significant elevation of RF titer. 2. There is a statistically insignificant correlation between age of RA manifestation and RF level. 3. The investigation of individual RF outcome shows that 54% of the patients have a relatively constant RF level, 15% tend to a decrease of the level of RF activity. Increased RF activity could only be demonstrated in 31% of the patients in the follow-up. 4. We more often observed a decrease of RF activity in RA cases with a disease manifestation < 30 y. We found no significant decrease in the follow-up in cases with manifestation > 60 y. 5. RA patients with a high level of RF activity (HAR > 1:512) have a significantly higher radiological progression index than cases with a low RF activity (HAR < 1:512).

[POEMS syndrome--a case report]. / Das POEMS Syndrom--Ein Fallbericht.

One rare case of POEMS syndrome is presented. In a 39-year-old male patient a progressive numbness in hands and feet developed within 5 years. Admission with increasing dyspnoea and lower leg edema. In swollen inguinal lymph nodes a lymphadenopathy with angiofollicular hyperplasia and vascular-plasmacellular proliferation was diagnosed and classified as Castleman-like histologic features. In os ilium an osteosclerotic plasmocytoma with restriction of kappa light chains was found. Potential pathomechanism of POEMS syndrome are discussed.