Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs.

OBJECTIVE: To investigate the risk of developing lower intestinal perforations (LIPs) in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ). METHODS: In 13 310 patients with RA observed in the German biologics register Rheumatoid Arthritis: Observation of Biologic Therapy, 141 serious gastrointestinal events possibly associated with perforations were reported until 31 October 2015. All events were validated independently by two physicians, blinded for treatment exposure. RESULTS: 37 LIPs (32 in the colon/sigma) were observed in 53 972 patient years (PYs). Only two patients had a history of diverticulitis (one in TCZ). Age, current/cumulative glucocorticoids and non-steroidal anti-inflammatory drugs were significantly associated with the risk of LIP. The crude incidence rate of LIP was significantly increased in TCZ (2.7/1000 PYs) as compared with all other treatments (0.2-0.6/1000 PYs). The adjusted HR (ref: conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs)) in TCZ was 4.48 (95% CI 2.0 to 10.0), in tumour necrosis factor-α inhibitor (TNFi) 1.04 (0.5 to 2.3) and in other biologic DMARDs 0.33 (0.1 to 1.4). 4/11 patients treated with TCZ presented without typical symptoms of LIP (acute abdomen, severe pain). Only one patient had highly elevated C reactive protein (CRP). One quarter of patients died within 30 days after LIP (9/37), 5/11 under TCZ, 2/13 under TNFi and 2/11 under csDMARD treatment. CONCLUSIONS: The incidence rates of LIP under TCZ found in this real world study are in line with those seen in randomised controlled trials of TCZ and higher than in all other DMARD treatments. To ensure safe use of TCZ in daily practice, physicians and patients should be aware that, under TCZ, LIP may occur with mild symptoms only and without CRP elevation.

[Prophylaxis and treatment of osteoporosis in patients with rheumatoid arthritis (ORA study)]. / Medikamentöse Osteoporoseprophylaxe und -Therapie bei Patienten mit Rheumatoider Arthritis (ORA-Studie).

OBJECTIVE: The aim of this study was to examine bone mineral density (BMD), frequency of osteopenia and osteoporosis in a representative sample of patients with rheumatoid arthritis (RA) and to describe chemoprophylaxis and treatment of osteoporosis compared to evidence-based guidelines. PATIENTS AND METHODS: In 2005 and 2006, 532 patients with RA (98 men, 434 women) aged 23-87 years were recruited from 9 German rheumatology centers. Clinical examination included a detailed documentation of osteoporosis medication. Dual-energy X-ray absorptiometry (DXA) was used to measure BMD at the lumbar spine and femoral neck. Osteopenia and osteoporosis were defined according to the criteria of the World Health Organization. RESULTS: Of the RA patients 29% had normal BMD at the spine and femoral neck, 49% of the patients had osteopenia and 22% met the criteria for osteoporosis at any site. Of the patients 60% were receiving medication for prophylaxis or therapy of osteoporosis, 38% calcium/vitamin D alone, 20% as combinations mostly of calcium/vitamin D + bisphosphonate, 1% received bisphosphonate only and 1% hormone replacement therapy. Although the frequency of osteoporosis showed no significant differences between male and female patients, women with RA used osteoporosis medication more often than men (63% versus 49%, χ²-test, p <0.05). A total of 101 RA patients (83 menopausal women, 6 premenopausal women, 12 men) received corticosteroids in a daily dose of 7.5 mg or less for at least 3 months and had DXA T-scores below -2.0 at any site. In this patient group 41% of the menopausal women, 17% of the premenopausal women and 42% of the male patients were reported to receive medication with calcium/vitamin D + bisphosphonate. Calcium/vitamin D was used by 35% of the menopausal women, none of the premenopausal women and 50% of the male patients and 18% of the menopausal women, 67% of the premenopausal women and 8% of men received no prophylaxis or treatment for osteoporosis. CONCLUSION: According to the DVO (German Society for Osteoporosis) guidelines for osteoporosis (2009) menopausal women with corticosteroid therapy < 7.5 mg per day for at least 3 months and DXA T-scores below -2.0 should receive treatment with bisphosphonate and calcium/vitamin D. The data show that there were still deficits concerning prophylaxis and treatment of osteoporosis in RA.

[Diagnosis and treatment of osteoporosis and rheumatoid arthritis in accordance with German guidelines. Results of a survey of patients, primary care physicians and rheumatologists]. / Diagnostik und Behandlung der Osteoporose bei rheumatoider Arthritis vor dem Hintergrund der Leitliniennutzung. Ergebnisse einer Befragung von Patienten, Hausärzten und Rheumatologen (ORA-Studie).

In a cross-sectional study the prevalence of osteoporosis and osteopenia in patients with rheumatoid arthritis (ORA study) was investigated. Additionally, patients, their family doctors and rheumatologists were surveyed on their awareness of osteoporosis in RA, prevention, diagnosis, treatment and use of guidelines.In the years 2005 and 2006 a total of 532 patients with RA (98 men, 434 women) aged 23-87 years were consecutively recruited from 9 German centers for rheumatology. Clinical examination included a detailed documentation of osteoporosis medication. Dual-energy X-ray absorptiometry (DXA) was used to measure bone mineral density (BMD) at the lumbar spine and neck of the femur. Questionnaires on osteoporosis were sent to 119 family doctors (87 men, 32 women) and 44 rheumatologists (30 men, 14 women).The survey showed that rheumatologists had a higher awareness of osteoporosis in RA and compared to family doctors they estimated a higher frequency and tested RA patients more often for osteoporosis. In line with osteoporosis guidelines rheumatologists and family doctors saw an indication for densitometry in RA patients on steroid therapy and/or low intensity trauma fractures. In contrast to the 2006 recommendations of osteoporosis guidelines 50% of family doctors and rheumatologists preferred bisphosphonate off-label-therapy for premeopausal women with RA and comorbid glucocorticoid-induced osteoporosis. On the other hand 50% of premenopausal RA patients with osteoporosis did not receive any osteoporosis medication.The survey revealed a high degree of guideline compliance in diagnosing osteoporosis in RA but deficits were observed in the administration of osteoporosis medication, especially in premenopausal women.

[Bone densitometry in inflammatory rheumatic diseases : Characteristics of the measurement site and disease-specific factors]. / Knochendichtemessungen bei entzündlich-rheumatischen Erkrankungen : Besonderheiten der Messorte und krankheitsspezifische Einflussfaktoren.

Bone densitometry should be performed earlier in patients with inflammatory arthritis, since factors such as inflammation and drug therapy, in particular treatment with glucocorticoids, have an important impact on the development of osteoporosis. DXA (Dual energy X-ray Absorptiometry) is considered the gold standard for bone densitometry. According to the German guidelines for osteoporosis, bone densitometry plays a crucial role in the choice of therapy.In patients with rheumatoid arthritis, measurement of peripheral bone (forearm) density in addition to lumbar spine and hip is recommended, since local bone loss is pathognomonic for this disease. DXA measurements of the hand enable the diagnosis of juxtaarticular osteoporosis at an earlier stage; however, this has not yet been established in routine practise.Bone measurement in patients with ankylosing spondylitis can be performed in the lumbar spine and the hip at disease onset. In systemic lupus erythematosus, bone loss is more frequent in patients with high inflammatory activity. Patients with psoriasis arthritis frequently have osteoporosis in the case of a destructive development of the joints.

Dose-related patterns of glucocorticoid-induced side effects.

OBJECTIVE: To identify patterns of self-reported health problems relating to dose and duration of glucocorticoid intake in unselected patients with rheumatoid arthritis from routine practice. METHODS: Data from 1066 patients were analysed. The clinical status and drug treatment were reported by the physician, health problems during the past 6 months by the patient using a comprehensive list of symptoms. Patients with ongoing glucocorticoid treatment for more than 6 months and current doses of less than 5, 5-7.5 and over 7.5 mg/day prednisone equivalent were compared with a group without any glucocorticoid treatment for at least 12 months. RESULTS: The frequency of self-reported health problems was lowest in the group without glucocorticoid exposition and increased with dosage. Two distinct dose-related patterns of adverse events were observed. A "linear" rising with increasing dose was found for cushingoid phenotype, ecchymosis, leg oedema, mycosis, parchment-like skin, shortness of breath and sleep disturbance. A "threshold pattern" describing an elevated frequency of events beyond a certain threshold value was observed at dosages of over 7.5 mg/day for glaucoma, depression/listlessness and increase in blood pressure. Dosages of 5 mg/day or more were associated with epistaxis and weight gain. A very low threshold was seen for eye cataract (<5 mg/day). CONCLUSION: The associations found are in agreement with biological mechanisms and clinical observations. As there is a paucity of real-life data on adverse effects of glucocorticoids prescribed to unselected groups of patients, these data may help the clinician to adapt therapy with glucocorticoids accordingly and improve the benefit-risk ratio.

Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial.

OBJECTIVE: To compare the efficacy and safety of subcutaneous (SC) versus oral administration of methotrexate (MTX) in patients with active rheumatoid arthritis (RA). METHODS: MTX-naive patients with active RA (Disease Activity Score in 28 joints >or= 4) were eligible for the study if they had not previously taken biologic agents and had not taken disease-modifying antirheumatic drugs for 2 weeks prior to randomization. Patients were randomly assigned to receive 15 mg/week of MTX either orally (2 7.5-mg tablets plus a dummy prefilled syringe; n=187 patients) or SC (prefilled syringe containing 10 mg/ml plus 2 dummy tablets; n=188 patients) for 24 weeks. At week 16, patients who did not meet the American College of Rheumatology criteria for 20% improvement (ACR20) were switched from 15 mg of oral MTX to 15 mg of SC MTX and from 15 mg of SC MTX to 20 mg of SC MTX for the remaining 8 weeks, still in a blinded manner. The primary outcome was an ACR20 response at 24 weeks. RESULTS: At week 24, significantly more patients treated with SC MTX than with oral MTX showed ACR20 (78% versus 70%) and ACR70 (41% versus 33%) responses. Patients with a disease duration >or= 12 months had even higher ACR20 response rates (89% for SC administration and 63% for oral). In 52 of the ACR20 nonresponders (14%), treatment was switched at week 16. Changing from oral to SC MTX and from 15 mg to 20 mg of SC MTX resulted in 30% and 23% ACR20 response rates, respectively, in these patients. MTX was well tolerated. The rate of adverse events was similar in all groups. CONCLUSION: This 6-month prospective, randomized, controlled trial is the first to examine oral versus SC administration of MTX. We found that SC administration was significantly more effective than oral administration of the same MTX dosage. There was no difference in tolerability.

[The mechanism of bone loss in rheumatoid arthritis. Description based on a case report]. / Mechanismen des Knochenmasseverlustes bei rheumatoider Arthritis. Darstellung anhand einer Kasuistik.

Various factors influencing bone turnover and bone loss in rheumatoid arthritis (RA) are illustrated using the example of a postmenopausal woman with a highly active RA. In particular, the relationships between disease activity, vitamin D metabolism, parathyroid hormone (PTH) levels and calcium metabolism are described. High disease activity is associated with low levels of 25-hydroxycholecalciferol, and especially of 1.25-dihydroxycholecalciferol. Despite vitamin D deficiency, PTH levels were decreased and histomorphometric investigation of the iliac crest biopsy showed severe osteoporosis but no signs of osteomalacia. Suppression of the inflammatory disease activity of RA led to a normalisation of the serum levels of 1.25-dihydroxycholecalciferol and PTH. This was associated with a reduction in the initially increased levels of bone specific alkaline phosphatase to normal values. This case report shows a close relationship between disease activity and bone turnover in RA and indicates that early investigation and therapy of disturbances of bone metabolism in RA are necessary.

[Insufficiency fractures in rheumatology. Case report and overview]. / Insuffizienzfrakturen in der Rheumatologie. Fallbeschreibung und Ubersicht.

Stress fractures occur as insufficiency fractures, with a prevalence of 0.8% in patients with rheumatological illness. The main sites of insufficiency fractures are the pelvis and sacrum, parts of the tibia and fibula that are close to the joints, and the calcaneus and hip. Since the painful symptoms overlap with the clinical picture of the painful joint diseases and because of the low sensitivity of conventional diagnostic X-ray, insufficiency fractures are not diagnosed directly or their diagnosis is delayed. The high sensitivity of computer tomography, skeletal scintigraphy and nuclear magnetic resonance imaging should be exploited in the diagnosis of insufficiency fractures. The case report presented describes insufficiency fractures of the distal right tibia and fibula in an elderly female patient with rheumatoid arthritis being treated with long-term glucocorticoids. In addition to advanced age, female gender, immobility and rheumatoid arthritis requiring long-term cortisone, there are further risk factors for insufficiency fractures: fluoride treatment over many years in the past, hypovitaminosis D3, renal failure. The DXA bone density values of the neck of the femur and the lumbar vertebrae do not show any osteoporosis, and the calcium concentration in the serum is low; phosphate is raised and parathormone is normal; osteocalcin, beta crosslaps and alkaline phosphatase are raised. Bone biopsy specimens taken from the iliac crest and the proximal femur and investigated for the purpose of differential diagnosis revealed renal osteopathy with secondary hyperparathyroidism and osteomalacia. In elderly patients with kidney failure, the possibility of renal osteopathy must be considered as the possible cause of reduced bone quality with a raised risk of insufficiency fractures, even when the parathormone levels are normal. In view of the frequency of osteopathies in rheumatological patients, osteology is of enormous significance in rheumatology.

[Antiosteoporosis medication: useful monitoring, and how long should such treatment be continued?]. / Osteoprotektive Medikation: sinnvolles Monitoring, wie lange therapieren?

The improved options for effective treatment of osteoporosis and the shift to treatment strategies based on each patient's absolute fracture risk raise new questions in daily clinical care. Which patient should have what osteoprotective therapy and when and for how long? What techniques can be used to assess the individual effects of novel therapeuties? Are the results yielded by these techniques affected by concomitant factors? What specific characteristics need to be taken account of in rheumatological clinics and how should we deal with these? What is the impact of patient compliance on the assessment of therapeutic effects? This review is intended to shed some light on these questions and on the new DVO guidelines in daily practice with reference to the ambulatory setting.

[Dose adjustment in patients treated with infliximab in routine rheumatologic care in Germany. Results from the Biologics Register RABBIT]. / Dosisanpassung bei Patienten mit rheumatoider Arthritis unter Therapie mit Infliximab in der rheumatologischen Versorgung in Deutschland. Ergebnisse aus dem Biologika-Register RABBIT.

OBJECTIVE: Data from international observational studies show that a considerable proportion of patients use higher dosages of infliximab (INF) than the usual 3 mg every 8 weeks used in Germany for treatment of rheumatoid arthritis. The Data are, however, inconsistent and vary between countries. Using data from the German Biologics Register RABBIT we investigated: (1) how dosage of INF develops during the first year of treatment in routine care, and (2) how dosage translates into clinical effectiveness. PATIENTS: We analysed data from 344 patients who started a treatment with INF at their inclusion into the register and who were observed for the subsequent 12 months. Mean dosage at 3 months (after the loading dose) was 3.2 mg/kg body weight/infusion and 3.3 mg/kg after 1 year. If we also consider shortening the infusion intervals, the mean dosages at the start and after 1 year were 4.0 mg/kg body weight every 8 weeks. RESULTS: Patients who were treated with low dosages of up to 3 mg/kg/8 weeks showed significantly less improvement (EULAR response) than those who were treated with higher dosages. CONCLUSIONS: The data show that German rheumatologists are aware of the high costs of treatment and try to use the lowest possible dosage. However, for a certain proportion of the patients this might be insufficient.