Ingiäld Hafström

EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases

Objective: To develop evidence-based recommendations for the management of systemic glucocorticoid (GC) therapy in rheumatic diseases. Methods: The multidisciplinary guideline development group from 11 European countries, Canada and the USA consisted of 15 rheumatologists, 1 internist, 1 rheumatologist–epidemiologist, 1 health professional, 1 patient and 1 research fellow. The Delphi method was used to agree on 10 key propositions related to the safe use of GCs. A systematic literature search of PUBMED, EMBASE, CINAHL, and Cochrane Library was then used to identify the best available research evidence to support each of the 10 propositions. The strength of recommendation was given according to research evidence, clinical expertise and perceived patient preference. Results: The 10 propositions were generated through three Delphi rounds and included patient education, risk factors, adverse effects, concomitant therapy (ie, non-steroidal anti-inflammatory drugs, gastroprotection and cyclo-oxygenase-2 selective inhibitors, calcium and vitamin D, bisphosphonates) and special safety advice (ie, adrenal insufficiency, pregnancy, growth impairment). Conclusion: Ten key recommendations for the management of systemic GC-therapy were formulated using a combination of systematically retrieved research evidence and expert consensus. There are areas of importance that have little evidence (ie, dosing and tapering strategies, timing, risk factors and monitoring for adverse effects, perioperative GC-replacement) and need further research; therefore also a research agenda was composed.

Leukotriene B4 — a stereospecific stimulator for release of lysosomal enzymes from neutrophils

Polynlorphonuclear (PMN) neutrophil granulocytes react with increased adherence, chemotaxis, degranulation, oxidative metabolism and bacterial killing after contact with substances generated in an inflammatory or infected site, e.g., the CSa-fragment and bacterial products, such as fMLP. Although critical for host defence, these mediators are also responsible for part of the tissue damage characterizing inflammation because of release of PMN Iysosomal enzymes and formation of toxic oxygen radicals [l-4]. A novel group of mediators of inflammation are called leukotrienes [5]. These are formed within PMNs after stimulation with fMLP or the calcium ionophore A 23 I87 by a lipoxygenase~dependent oxygenation of arachidonic acid. The generated epoxide leukotriene A4 (LTA4) is unstable and converted to leukotriene B4 (LTB4, 5,12-dihydroxyeicosatetraenoic acid) by enzymatic hydrolysis. Two other 5 ,12-dihydroxy isomers {compounds I and ZI) can also be formed by a non-enzymatic hydrolysis of LTA4. Further, leukotriene C4 (LTC& is formed from LTA4 by adding glutathione, and can be metabolized to LTD4 by elimination of its y-glutamyl residue. LTC4 and LTD4 have been identified in SRS-A from various sources, beirlgpotent bronchoconstri~tors and increasing permeability of the microvasculature

Remission achieved after 2 years treatment with low-dose prednisolone in addition to disease-modifying anti-rheumatic drugs in early rheumatoid arthritis is associated with reduced joint destruction still present after 4 years: an open 2-year continuation study

Objective: To evaluate if remission induced by low-dose prednisolone during the first 2 years of rheumatoid arthritis (RA) in the BARFOT glucocorticoid (GC) study had a sustained effect on radiological damage for a total of 4 years. Methods: A total of 150 of 211 eligible patients with RA who had been randomised to the 7.5 mg prednisolone group (P) or no prednisolone group (NoP) in addition to the initial disease-modifying antirheumatic drugs were included. Radiographs of hands and feet were scored using the Sharp–van der Heijde scoring method. A patient was considered to be in remission if the 28-joint count disease activity score was <2.6. Results: Mean (SD) age was 53 (14) and 57 (12) years for the patients in the P and NoP groups, respectively. 64% were female, 64% rheumatoid factor positive, and disease duration at baseline was 6 months. At 2 years the proportion of patients in remission in the P and NoP groups was 55 vs 30%, pu200a=u200a0.003. Longitudinal analysis showed that over the entire course of the disease, patients on prednisolone had a higher probability of being in remission. Patients in remission at 2 years, compared with those not in remission, had significantly lower total Sharp score, erosion score and joint space narrowing score at 2 and 4 years. The changes in bone mineral density during the 4 years did not differ between those in remission and those with active disease, and were similar in the two treatment groups. Conclusions: Prednisolone 7.5 mg daily in addition to disease-modifying anti-rheumatic drugs increases the rate of remission in patients with early RA, which has a beneficial and sustained effect on radiological damage.

Hand bone loss measured by digital X-ray radiogrammetry is a predictor of joint damage in early rheumatoid arthritis.

Objective: The aim of this study was to evaluate whether loss of bone measured by digital X-ray radiogrammetry (DXR) of hands early in the course of rheumatoid arthritis (RA) may predict future radiographic joint damage after 1 and 2 years. Methods: A total of 166 patients with early RA, who were part of the Better Anti-Rheumatic FarmacOTherapy (BARFOT) low-dose prednisolone study, were included. The patients had been randomized to treatment with 7.5 mg prednisolone daily or no prednisolone when they started with their first disease-modifying anti-rheumatic drug (DMARD) therapy. Radiographs of hands and feet were taken at baseline and after 1 and 2 years and assessed by the van der Heijde modified Sharp (vdH-S) score. Hand bone density (HBD) was measured on the same radiographs by DXR. Changes in HBD and hand bone loss (HBL) were calculated. HBL was defined as a change in DXR bone mineral density (DXR-BMD) during the first year by more than 0.0048 g/cm2. Results: HBL was found in 64% of the patients. Patients with HBL had radiological progression significantly more often than patients without (80% vs. 57%, p=0.012). Patients not treated with prednisolone had HBL more often than patients with this treatment (83% vs. 44%, p=0.001). In multiple regression analyses, HBL and change in DXR-BMD during the first year proved to be independent predictors of radiological progression. Conclusions: Loss of bone measured by DXR was found to be an independent predictor of radiological joint damage and may thus be an additional tool in the process of treatment decision in early RA.

Modulation of Neutrophil Functions by Auranofin

Auranofln, a new anti-arthritic oral gold compound, was studied with regard to its effects on the functions of the neutrophil polymorphonuclear (PMN) granulocyte. Firstly, human PMNs were preincubated in vitro with auranofln in concentrations ranging from 1-4 µ;g/ml, whereafter PMN functions in vitro were assayed. Following such exposure, PMN adherence to nylon fibres was significantly increased and this enhancement was most pronounced at the lower auranofln concentrations (p<0.001). A biphasic response was noted with regard to enzyme release and chemiluminescence. Thus, following stimulation with formyl-methionyl-leucyl-phenylalanine (fMLP) PMNs pretreated with 1µ /ml of auranofln released 51% more lysozyme than did control cells, whereas the release was restricted to 26% when 4 µ /ml of auranofln was used. However, auranofln did not affect enzyme release induced by the ionophore A 23187. The chemiluminescence evoked by both particulate (Staph, aureus) and soluble (ConA) stimuli was increased by 4 and 28...

Rat neutrophil function, and leukotriene generation in essential fatty acid deficiency

Since the essential fatty acid linoleic acid is the precursor of arachidonic acid and thus of leukotriene B4 (LTB4), essential fatty acid deficiency (EFAD) may result in decreased synthesis of this stimulator of neutrophil granulocyte functions. Peritoneal and blood neutrophils from rats fed a diet with only 0.3% of energy requirements as linoleic acid and exhibiting biochemical evidence of EFAD showed substantial functional impairments compared to neutrophils from rats maintained on a diet with 3% of the energy requirement as linoleic acid. Oxidative burst activation (assessed by chemiluminescence), chemotaxis and aggregation were impaired upon stimulation with formylpeptides or the ionophore A23187. In contrast, these functions were intact on stimulation with exogenous LTB4. Chemiluminescence was slightly but not significantly enhanced in EFAD rat neutrophils compared to controls when stimulated with phorbol myristate acetate (PMA). There were no differences between EFAD and control peritoneal neutrophils in the number of f-metleu-phe (fMLP) receptors, or in their affinity for the ligand, assessed with fML(3H)P. The fraction of responding cells also were similar, assessed with dichlorofluorescein diacetate fluorescence. Moreover, the endogenous LTB4 production in response to A23187 or fMLP was decreased by 57.7% and 63.5%, respectively, in EFAD peritoneal neutrophils. Thus, EFAD was associated with reductions of LTB4 production and neutrophil responsiveness to A23187 and formylpeptides but not to LTB4 or PMA, which supports the hypothesis that endogenous LTB4 may contribute to the activation of neutrophil functions involved in inflammation and host defense.

Effect of sulphasalazine and sulphapyridine on neutrophil superoxide production: role of cytosolic free calcium.

As the neutrophil granulocyte plays an important part in rheumatoid inflammation the effect of sulphasalazine on neutrophil function was studied. The results show that sulphasalazine, and its metabolite sulphapyridine, inhibit neutrophil superoxide production elicited by the receptor mediated stimulus N-formyl-methionyl-leucyl-phenyl-alanine (fMLP) and by the calcium ionophore A23187. This effect seems to be dependent on inhibition of intracellular Ca++ increase as both substances reduce this increase upon cell activation with fMLP and A23187. Sulphasalazine and sulphapyridine do not inhibit superoxide production after stimulation with the ester phorbol myristate acetate, a stimulus response coupling which is independent of intracellular Ca++ increase. The reported inhibition of superoxide generation may explain, at least partly, the antirheumatic property of sulphasalazine.

Physiotherapy in subtropic climate improves functional capacity and health‐related quality of life in Swedish patients with rheumatoid arthritis and spondylarthropathies still after 6 months

Objective: The objective was to prospectively evaluate the short as well as the long‐term effects of intensive physiotherapy in a stable, sunny and warm climate on physical function and health related quality of life in patients with rheumatoid arthritis (RA) and spondylarthropathies (SpA). Methods: Ninety‐three Swedish patients with RA and SpA receiving physiotherapy for 4 weeks in Israel or Tenerife were followed for 6 months. Physical function was evaluated by the Swedish version of Stanford Health Assessment Questionnaire (HAQ) and quality of life by the Nottingham Health Profile (NHP) questionnaire. Results: There were significant improvements in HAQ‐scores and global NHP‐scores as well as all subcategories of NHP immediately after the treatment abroad, effects that were still measurable after six months. At that time point nearly half of the patients had clinically meaningful reduction of HAQ‐scores (≥0.25). Conclusion: Physiotherapy in a warm and stable climate, with many hours of daily sunshine, is a valuable treatment complement for Swedish patients with RA and SpA.

Rheumatoid factor and anti-CCP do not predict progressive joint damage in patients with early rheumatoid arthritis treated with prednisolone: a randomised study

Objective To analyse if predictors of radiographic progression differ between patients treated with or without prednisolone in early rheumatoid arthritis (RA). Radiographs of hands and feet were assessed using the modified Sharp/van der Heijde score and radiographic progression was defined as an increase in the total Sharp score above 5.8 (the smallest detectable change). Design Prospective, randomised study of patients with early RA. Setting Secondary level of care; six participating centres from southern Sweden; both urban and rural populations. Participants In all, 225 patients, 64% women, with a diagnosis of RA according to the American College of Rheumatology criteria, were included if they were between 18 and 80u2005years of age and had a disease duration of less than 1u2005year. Intervention The patients were randomised to 7.5u2005mg prednisolone daily for 2u2005years (P-group; n=108) or no prednisolone (NoP-group; n=117) when they started with their first disease-modifying anti-rheumatic drug and were prospectively followed for 2u2005years. Results The frequency of patients with radiographic progression after 2u2005years was 26% in the P-group and 39% in the NoP-group (p=0.033). Relevant interactions between treatment and rheumatoid factor (RF) (p=0.061) and between treatment and anti-cyclic citrullinated peptide 2 (anti-CCP) (p=0.096) were found. RF and anti-CCP independently predicted radiographic progression only in the NoP-group, OR (95% CI) 9.4 (2.5 to 35.2), p=0.001 and OR (95% CI) 8.7 (2.5 to 31.3), p=0.001, respectively. Conclusions The presence of RF and anti-CCP predicted radiographic progression in patients not treated with prednisolone but failed to predict progression in patients treated with this drug. The data suggest that early treatment with prednisolone may modulate not only inflammation but also autoimmunity-associated pathogenetic mechanisms. Trial registration number ISRCTN20612367.

Effects of auranofin on leukotriene production and leukotriene stimulated neutrophil function

Arachidonic acid is metabolized in neutrophils by lipoxygenase to leukotrienes, which are suggested to play a central role in inflammation. The antirheumatic drug auranofin (4 μg/ml) was found not to inhibit neutrophil production of the lipoxygenase products 5-HETE, 15-HETE and LTB4,in vitro when stimulated with the calcium ionophore A23187. Auranofin, however, modulated neutrophil aggregation, enzyme release and chemotaxis induced by LTB4. The results suggest that auranofin may exert some of its antirheumatic effects through affecting neutrophil responses to leukotrienes.