Assessment of interactions and dosage recommendations of synthetic DMARDs-Evidence-based and consensus-based recommendations based on a systematic literature search.

Conventional synthetic (cs) and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARD) have potential interactions with a multitude of drugs. Furthermore, they sometimes have a lower therapeutic index, particularly in cases of limited organ functions. The aim of this work was to establish evidence-based recommendations on the therapeutic use of DMARDs in the context of drug interactions and dosage recommendations. A systematic literature search was carried out on the issue of drug interactions and dosages in cases of patients with limited kidney function and higher age and suffering from rheumatoid arthritis. A total of 2756 scientific publications were screened and 154 selected of which 68 were scrutinized in detail. Furthermore, the respective product information was also analyzed. A multitude of possible interactions of synthetic DMARDs with different drugs were detected, which were then assessed with respect to the clinical significance and consequences. A consensus process led to making recommendations with which the interactions were classified: A: dangerous combination, B: avoid combination (if possible, pausing DMARD treatment), C: possible combination requiring increased monitoring and potential adjustments in dosage and D: pharmacological interaction without relevance in DMARD standard doses. Apart from that dosage recommendations were established for each csDMARD and tsDMARD depending on kidney function and age. There are 3 primary recommendations and 11 core recommendations on interactions and dosages of csDMARDs and tsDMARDs meant as a practical help for therapeutic decision making and to improve safety in the treatment of rheumatoid arthritis.

[Assessment of interactions and dosage recommendations of synthetic DMARDs-Evidence-based and consensus-based recommendations based on a systematic literature search]. / Bewertung von Wechselwirkungen und Dosierungsempfehlungen von synthetischen DMARDs ­ Evidenz- und konsensbasierte Empfehlungen auf Basis einer systematischen Literatursuche.

Conventional synthetic (cs) and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARD) have potential interactions with a multitude of drugs. Furthermore, they sometimes have a lower therapeutic index, particularly in cases of limited organ functions. The aim of this work was to establish evidence-based recommendations on the therapeutic use of DMARDs in the context of drug interactions and dosage recommendations. A systematic literature search was carried out on the issue of drug interactions and dosages in cases of patients with limited kidney function and higher age and suffering from rheumatoid arthritis. A total of 2756 scientific publications were screened and 154 selected of which 68 were scrutinized in detail. Furthermore, the respective specialist subject information was also analyzed. A multitude of possible interactions of synthetic DMARDs with different drugs were detected, which were then assessed with respect to the clinical significance and consequences. A consensus process led to making recommendations with which the interactions were classified: A: dangerous combination, B: avoid combination (if possible, pausing DMARD treatment), C: possible combination requiring increased monitoring and potential adjustments in dosage and D: pharmacological interaction without relevance in DMARD standard doses. Apart from that dosage recommendations were established for each csDMARD and tsDMARD depending on kidney function and age. There are 3 primary recommendations and 11 core recommendations on interactions and dosages of csDMARDs and tsDMARDs meant as a practical help for therapeutic decision making and to improve safety in the treatment of rheumatoid arthritis.

[Rheumatology in German MD curricula]. / Rheumatologie im Medizinstudium.

Transmitting a substantial amount of basic knowledge in Rheumatology to all medical students is essential for the future medical care of patients with rheumatic diseases for two reasons: on the one hand, future general practitioners will need to master the patterns of rheumatic diseases to recognize them fast enough in new-onset patients and to refer them in time and directly to rheumatologists. On the other hand, the shortage of rheumatologists can only then be relieved in the future when we are able to inspire enthusiasm for our specialty. Adequate rheumatological structures are established only in some of the German faculties of medicine. Structural improvements happen in small steps only but were achieved at several sites. The better the local structures, the higher the chances of committed university teachers in rheumatology to reach all medical students. Probably from 2026 onwards, the learning objectives relevant for examinations will be defined by the national competence-based catalogue of learning objectives in medicine (NKLM), which is currently in the final stages of completion together with the German Federal Institute for Medical and Pharmaceutical Examinations (IMPP). It now appears that systemic autoimmune diseases and inflammatory rheumatic diseases are adequately depicted in this catalogue. If this is achieved, students will know more about these diseases in the future and will diagnose them faster in patients. Work on the NKLM is therefore of highest importance. In addition to the work on the learning objectives, up to date learning materials are required, which have to be available throughout Germany. A Rheumatology script just finished by the committee for medical student education of the German Society of Rheumatology (DGRh) and now available on the DGRh homepage should close this gap.

Size matters: observations regarding the sonographic double contour sign in different joint sizes in acute gouty arthritis.

OBJECTIVE: In distinguishing urate arthritis (UA) from non-crystal-related arthritides, joint sonography including the detection of the double contour sign (DCS) and hypervascularization using power Doppler ultrasound (PDUS) is an important step in the diagnostic process. But are these sonographic features equally reliable in every accessible joint under real-life conditions? METHODS: We retrospectively analyzed 362 patients with acute arthritis and evaluated the DCS and the degree of PDUS hypervascularization in patients with gout and in those with arthritis other than urate arthritis (non-UA). We classified all joints into the groups small, medium, and large. Sensitivities, specificities, positive and negative predictive values (PPV/NPV), and a binary regression model were calculated. We also evaluated the influence of serum uric acid levels (SUA) on the presence of a DCS in each joint category. RESULTS: Sensitivity of the DCS in gout was 72.5% in the entire cohort, 66.0% in large, 78.8% in medium, and 72.3% in small joints. In wrist joints the DCS sensitivity maxed at 83.3%, with a specificity of 81.8%. The lowest rates of DCS sensitivity were found in gout patients with elbow joint involvement (42.9%). In all joints except metatarsophalangeal joint 1 (MTP-1), the incidence of a DCS increased by the increment of SUA levels above 7.5 mg/dl (p < 0.001). PDUS signals were most commonly found in medium and small joints and were only scarce in large joints, independent of the underlying diagnosis. CONCLUSIONS: In our study we detected different rates of accuracy regarding DCS and PDUS in patients with acute arthritis. The best results were seen in medium-size joints, especially wrists.

[Sarcoidosis : Renal manifestations]. / Sarkoidose : Renale Manifestationen.

Renal involvement in sarcoidosis is much more common than generally assumed from old epidemiological studies and is often only detected when actively searched for. Many patients with renal sarcoidosis present with no or only few symptoms. The diagnostic work-up of sarcoidosis should always include a possible renal involvement. In cases of impaired renal function, proteinuria or a pathological urine sediment, a renal biopsy specimen should be obtained to assess the type, severity and prognosis of the kidney disease. Treatment is primarily based on the use of corticosteroids. Steroid-sparing agents, such as disease-modifying antirheumatic drugs and infliximab can be applied; however, the evidence for efficacy of these therapies is mostly based on case series and expert opinions. Discontinuation of immunosuppression therapy bears a high risk of relapse.

[Rheumatology - Integration into student training (RISA) : Current structure of clinical rheumatology in German universities (RISA III)]. / Rheumatologie - Integration in die studentische Ausbildung (RISA) : Zur aktuellen Struktur der internistischen Rheumatologie an deutschen Hochschulen (RISA III).

The German Society of Rheumatology and the Committee for Student Training investigated what effects the structures in university medicine have on student teaching. In February 2014 a questionnaire was sent to the teaching staff and Deans of each of the 37 medical faculties. Of the locations seven were classified as being independent rheumatological university hospitals and nine universities had a W2/W3/C3 grade professor as head of a department of clinical rheumatology but answerable to superiors. In the 37 faculties in Germany the proportion of lecture hours, the proportion of obligatory lecture hours, the number of hours for practical exercises and the number of hours for bedside teaching were distributed very differently and as a rule higher in universities with academic freedom. Not all medical faculties have obligatory teaching in the field of clinical rheumatology. On average medical students see five patients with rheumatological symptoms during their studies. In summary, over the past years it has not been possible to successfully utilize the great importance of rheumatology for society and the innovation potential of this discipline in order to improve the integration of clinical rheumatology into universities.

Nephrotoxicity of ibandronate and zoledronate in Wistar rats with normal renal function and after unilateral nephrectomy.

A previous animal study compared the nephrotoxic effect of ibandronate (IBN) and zoledronate (ZOL), but interpretation of these study results was limited because of the model of minimal nephrotoxic dosage with a dosage ratio of 1:3. The present study investigated the nephrotoxicity of ibandronate and zoledronate in a 1.5:1 dose ratio, as used in clinical practice and compared the nephrotoxicity in rats with normal and with mildly to moderately impaired renal function. We compared rats with normal renal function (SHAM) and with impaired renal function after unilateral nephrectomy (UNX), treated either with ibandronate 1.5mg/kg, zoledronate 1mg/kg or placebo once (1×) or nine (9×) times. Renal function and markers of tubular toxicity were measured over a 27 week period. After last bisphosphonate treatment the rats were sacrificed and kidneys examined histologically. All bisphosphonate treated animals showed a significant tubular toxicity, which was temporary except in the ZOL-UNX-9×-group. Also the renal function was only transiently reduced except in the ZOL-UNX-9×-group. Histologically, bisphosphonate treatment led to cortical tubuloepithelial degeneration/necrosis and medullary tubuloepithelial swelling which were slightly more pronounced in ibandronate treated animals, when compared to zoledronate treated animals, especially with impaired renal function. In contrast to the previous study we found a similar nephrotoxicity of ibandronate and zoledronate in rats with normal renal function. In rats with impaired renal function the peak of toxicity had not even been fully reached until end of experiment in the zoledronate treated animals. The peak of toxicity seems to be more severe and delayed in rats with impaired renal function compared with rats with normal renal function.

[Dosage and toxicity of antirheumatic drugs in renal insufficiency]. / Dosierung und Toxizität von Antirheumatika bei Niereninsuffizienz.

BACKGROUND: Patients with inflammatory rheumatic diseases frequently have a reduced renal function. The risk of adverse events is increased in these patients and treatment options in patients with rheumatic disease and renal failure are poorly studied. METHODS: A selective literature search was carried out for pharmocokinetics, dosage and toxicity of antirheumatic drugs in patients with renal insufficiency. RESULTS: The use of nonsteroidal anti-inflammatory drugs (NSAID), cyclooxygenase(COX)-2 inhibitors, gold and cyclosporine is limited in renal insufficiency due to nephrotoxicity. Methotrexate should not be used in patients with a glomerular filtration rate (eGFR) < 45 ml/min, because of the unpredictable pharmacokinetics with a risk for fatal pancytopenia. The dosage of sulfasalazine, azathioprine, mycophenolate mofetil, cyclophosphamide and antimalarial drugs should be reduced in patients with moderate and severe renal insufficiency. In contrast, leflunomide and numerous biologics can be used without dosage modification; however, biologics with a molecular weight < 60 kDa (e.g. anakinra) are an exception and should be reduced in patients with renal insufficiency. Overall, there are only limited data on the use of biologics in this population. Numerous comorbidities and the high risk for infection should be kept in mind when patients with rheumatic disease and renal failure are treated with immunosuppressive drugs. CONCLUSION: Further studies are necessary to obtain more evidence on the use of disease-modifying antirheumatic drugs (DMARD) and biologics in patients with renal insufficiency.

Renal sarcoidosis: epidemiological and follow-up data in a cohort of 27 patients.

BACKGROUND: Renal sarcoidosis (RS) is a possible manifestation of systemic sarcoidosis. The clinical presentation can range from asymptomatic individuals up to acute renal failure with the necessity of renal replacement therapy. The definite diagnosis must be established by renal biopsy. OBJECTIVES: Demonstration of clinical characteristics and effectiveness of steroid treatment. METHODS: We present a single center study of 27 patients with histologically proven RS. Firstly, we elaborate on descriptive features such as extra-renal organ involvement, calcium levels, renal function, proteinuria and histological subtypes and provide an histological assessment of renal damage. Secondly, we present follow-up data over a period of 2 years or more. RESULTS: Non-granulomatous tubulointerstitial nephritis (ngIN) was the most common histological entity (44%), followed by granulomatous IN (GIN, 30%), IgA-GN (26%) and nephrocalcinosis (11%). Under treatment with oral prednisone mean eGFR significantly improved from 38 ± 21 ml/min to 57 ± 26 ml/min and proteinuria decreased from 981 ± 304 mg/24 hrs to 176 ± 77 mg/24 hrs at the end of follow-up. In total, 62.5% of patients responded to therapy. CONCLUSIONS: We demonstrated that GIN is more often associated with advanced stages of renal insufficiency than any other histological manifestation of RS. Furthermore, prednisone therapy is effective in improving eGFR and in reducing total urinary protein secretion. We suggest that the key prognostic factor for renal survival in RS is the early response to treatment.

Bisphosphonate treatment and renal function in 201 myeloma patients undergoing stem cell transplantation.

Administration of bisphosphonates (BPs) is an essential supportive treatment for reducing bone-related complications in cancer. Deterioration of renal function is one possible side effect of BPs as well as a clinical feature in multiple myeloma. It has been suggested that the nephrotoxicity of different BPs may differ. We performed a retrospective evaluation of renal function in 201 myeloma patients undergoing myeloablative chemotherapy and treatment with ibandronate (I), pamidronate (P), or zoledronate (Z) for up to 36 months. There was no significant deterioration in mean creatinine clearance (CreaCl) in the entire cohort. The percentage of patients experiencing a decrease in CreaCl ≥ 25 % from baseline was 33.0 % in the I group, 44.4 % in the P group and 21.4 % in the Z group, respectively. CreaCl at baseline (P < 0.0001), relapse/progression (P = 0.0019), proteinuria at baseline (P = 0.039), age (P = 0.0031) were identified as significant independent predictors of decrease in renal function. In both descriptive multivariant analyses, we found no evidence of an advantage of any particular BP with respect to effects on renal function. In line with these data, in a subgroup of 90 patients with a baseline CreaCl <90 ml/min, no significant difference was evident between the cohorts of patients treated with different BPs. Regular treatment with the BPs I, P and Z in myeloma patients undergoing intensive chemotherapy appear to be equally safe for up to 3 years in terms of nephrotoxicity.

Determination of renal tissue ibandronate levels in rats with normal and mildly impaired renal function.

BACKGROUND: After entering the blood, bisphosphonates are immediately bound to bone or excreted unchanged by the kidney. During renal excretion about 0.5% of administrated dosage remains in kidney tissue. The renal tissue level of bisphosphonates (RTL) decreases over time and remains at about 0.15% after 3weeks, but the influence of renal insufficiency (RI) is unclear. METHOD: We investigated the influence of mild to moderate RI on RTL of ibandronate (IBD). First a method for determination of RTL was implemented and validated. We measured RTL in rats with normal renal function (SHAM) and after unilateral nephrectomy (UNX). In each case one SHAM and one UNX groups received one or alternatively 9 times every 3weeks a dosage of 1.5mg/kg IBD. After the last dosage the rats were sacrificed and RTL of IBD were determined. RESULTS: In SHAM-rats IBD concentrations increased from 272.7ng/g kidney after one injection to 428.9ng/g kidney after nine injections (p<0.0001). RTL in UNX rats likewise increased significantly (p<0.0001) from 289.9ng/g kidney to 520.2ng/g kidney. CONCLUSION: Our study found a 1.6 fold increase of RTL in SHAM rats and a 1.8 fold increase of RTL in UNX rats after nine versus one injection. As steady state is generally reached after five half-lives we anticipate no further accumulation on continued treatment.

Swollen joint count in psoriatic arthritis is associated with progressive radiological damage in hands and feet.

OBJECTIVES: Psoriatic arthritis (PsA) may progress to joint damage. Determining clinical predictors of joint damage assessed by radiography is important. The aim of this study was to determine clinical factors as possible predictors for radiological damage in hands and feet of PsA patients with a 12-month follow-up. METHODS: We conducted a retrospective study on 53 PsA patients who were taking disease-modifying anti-rheumatic drugs (DMARDs) and/or tumour necrosis factor (TNF)-alpha-blockers at a fixed dosage. The patients were observed in 118 follow-up visits (intervals of 12 months ± 3 months), according to a clinical and radiological protocol which included the documentation of the number of swollen and tender joints in hands and feet, the applied therapy, psoriasis, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and global health assessment. Outcome was defined as radiographic damage of hands and feet (Ratingen score). For the statistical analysis the Chi-Square test for 2x2 crosstables (with Fisher's correction, as required) was used. RESULTS: Progressive radiological damage was more frequent among patients with an increasing swollen joint count (8 of 26 visits; 30.8%) than among those with a stable or decreased number of swollen joints (5 of 89 visits; 5.6%; p=0.001). The analysis of the patients stratified into the different treatment modalities resulted in a significant higher rate of radiological progress (20.8%) in patients on DMARD therapy compared with TNF-alpha blocking agents (0%) (p=0.009). CONCLUSIONS: During a 12-month follow-up of PsA patients, an increasing number of swollen joints heralds progression of radiological damage. TNF-alpha-blocker therapy appears to be superior to DMARDs in the protection from radiological progress.

[Female patient with Sjoegren's syndrome and cardiolipin antibodies]. / Patientin mit Sjögren-Syndrom und Kardiolipinantikörpern.

Cross-reactions with cardiolipin antibodies and serological lues tests are common. We examined a 37 year old patient with neurological symptoms and signs of Sjoegren's syndrome and secondary antiphospholipid syndrome. But the lues screening test was also positive and the serological tests following approved the lues infection. When an autoimmune disease is diagnosed with the presence of cardiolipin antibodies we recommend also testing for treponema pallidum as a possible disease.

Neurologic complications of Churg-Strauss syndrome--a prospective monocentric study.

BACKGROUND: Churg-Strauss syndrome (CSS) is a rare systemic vasculitis. Case series with a focus on neurologic involvement are not common. With this study, we intended to evaluate the frequency and types of neurologic manifestations and complications at time of diagnosis and during follow-up of patients with CSS. METHODS: In this monocentric study, consecutive patients of our hospital with first diagnosis of CSS based on the criteria of the American College of Rheumatology were included between 2001 and 2007. Each patient underwent a periodic follow-up with clinical and electrophysiologic examination. Data were obtained prospectively. RESULTS: Fourteen patients were included. All patients had a hypereosinophilia and a history of asthma. Twelve of 14 patients had a neurologic involvement, mainly as an acute or subacute multiplex mononeuropathy (eight patients) or an axonal polyneuropathy (three patients). Three patients suffered from a neuropathy of cranial nerves, and two patients had a cerebral infarct. Mean follow-up period was 31 months. With immunosuppressive therapy, 13 patients had no additional neurologic complications, one patient suffered from a cerebral infarct. Initial neurologic symptoms as a result of peripheral neuropathy improved, but sequelae of axonal damage were persistently detectable. CONCLUSIONS: Even at time of diagnosis of a CSS, neurologic manifestations are common, especially as a multiplex mononeuropathy. With a consequent immunosuppressive therapy, new neurologic complications can be avoided for the most part.

Treatment of reduced bone density with ibandronate in dialysis patients.

Bisphosphonates inhibit bone resorption and are widely used to treat osteolytic metastases and osteoporosis. Renal osteodystrophy patients have continuous bone loss due to chronically elevated parathyroid hormone (PTH). In this open-label study, ibandronate was evaluated for the treatment of reduced bone density in renal osteodystrophy. Patients (n=16) with end-stage renal disease (ESRD) and regular hemodialysis schedules were recruited. All patients had low bone mineral density (BMD; lumbar spine T-score <-1.0) and elevated PTH levels (>2-fold higher than normal). Patients received ibandronate 2 mg every 4 weeks for 48 weeks. Serum levels of markers of bone turnover, calcium, phosphate and magnesium were determined (week 0 [prior to treatment] vs. at week 48). BMD (n=11) increased significantly from 88.94 +/- 31.68 mg/mL calcium hydroxylapatite (CaHA) to 93.51 +/- 35.36 mg/mL CaHA (p=0.032). T-scores increased significantly from -3.08 +/- 1.11 to -2.78 +/- 1.27 (p<0.01). The mean PTH level initially increased before dropping to 18.99 pmol/L at week 48 (7.99% decrease vs. week 0; not significant). Bone turnover markers decreased, whereas calcium and magnesium levels remained stable and within normal ranges. Phosphate levels were variable throughout the study. Two patients did not complete the study, and 3 patients died due to concomitant cardiovascular disease. Calcitriol dosage increased from 1.5 to 1.83 microg/week. In patients with renal osteodystrophy and ESRD, ibandronate significantly increased BMD and decreased bone turnover.

[Therapy of hypercalcemia with ibandronate in case of acute renal failure]. / Therapie der Hyperkalzämie mit Ibandronat bei akuter Niereninsuffizienz.

Hypercalcaemia is a common complication of malignancies associated with bone destruction. Besides, benign diseases as sarcoidosis or hyperparathyroidism may lead to hypercalcaemia. The main principles of modern therapy contain a forced diuresis as well as the application of bisphosphonates. Latter substances bear the danger of developing a renal insufficiency. Here, we report the case of a female patient, suffering from primary hyperparathyroidism with severe hypercalcaemia and calcium levels up to 6 mmol/l, who developed acute renal failure. We treated the patient with forced diuresis and repeated infusions of ibandronate (5 x 6 mg ibandronate). Even if lowering the serum levels of calcium only for a short time after each application, yet we could improve renal function by these means. Only after performing a parathyroidectomy, we could see a sustained decline of calcium levels. This case report supports the results of other publications, that have reported the missing nephrotoxic effect of ibandronate compared to other bisphosphonates.

High bone-binding capacity of ibandronate in hemodialysis patients.

Bisphosphonates are a potential therapy for osteoclast-mediated bone disease, such as renal osteodystrophy. This study evaluated ibandronate bone-binding in patients with secondary hyperparathyroidism and renal osteodystrophy and examined whether there is a correlation with bone metabolism parameters. Sixteen patients with end-stage renal disease and secondary hyperparathyroidism receiving regular hemodialysis were recruited to this 12-week trial. Intravenous ibandronate 2 mg was administered for 5 min every 4 weeks directly after hemodialysis. Ibandronate levels were measured 15 min after infusion and at trough levels before the next hemodialysis. Serological markers of bone metabolism were also measured. After the first infusion, the peak ibandronate level was 154 +/- 75.1 ng/ml and the trough level was 2.7 +/- 1.7 ng/ml. At week 12, peak and trough ibandronate levels were 164.8 +/- 89.9 ng/ml and 3.2 +/- 2.6 ng/ml, respectively. Ibandronate bone uptake was 98.0% at first application and 98.4% at week 12. In patients with remaining diuresis, ibandronate urine excretion was < 0.001% of the administered dose. There was no correlation of ibandronate bone-binding with parameters of osteoclast activity or parathyroid hormone (PTH). The correlation with markers of osteoblast activity was significant but weak. Ibandronate had a bone-binding capacity of approximately 98% in hemodialysis patients. After repeated dosing ibandronate bone-uptake remained stable and was independent of osteoclast activity or PTH levels. Due to the high bone-binding of ibandronate in these patients, a 2 mg dose of intravenous ibandronate is equivalent to a 4-5 mg dose of ibandronate in patients with normal renal function.

Therapy of IgA nephropathy with mycophenolate mofetil--report of 3 cases.

Mycophenolate mofetil is an immunosuppressive agent in transplantation which inhibits the purin neogenesis. Proliferating lymphocytes are suppressed and antibody production is decreased. Many cases of successful therapy in different kidney diseases are reported, such as diffuse proliferative lupus nephritis, pauci-immune necrotizing glomerulonephritis, focal segmental glomerular sclerosis and IgA nephropathy. We report 3 patients with IgA nephropathy who were treated with mycophenolate mofetil for more than 1 year. In all patients, proteinuria decreased significantly and the renal function remained stable. In 2 patients, kidney biopsy was repeated after 12 months and 18 months, respectively. There were no histological signs of progression of the disease. Two patients developed infections during treatment. One patient had a pneumonia, and a second patient an infection with varizella zoster. Based on our data, mycophenolate mofetil can be a potential treatment of IgA nephropathy. Further controlled studys are warranted to investigate the role of mycophenolate mofetil in IgA nephropathy.