Regional migratory osteoporosis in a patient with ankylosing spondylitis.

We report the first case of regional migratory osteoporosis (RMO) in a patient with ankylosing spondylitis (AS). This middle-aged man suffered from an acute onset of knee pain that increased on weight bearing, followed by ankle pain. The diagnosis of RMO was confirmed using magnetic resonance imaging (MRI), after exclusion of other causes of knee pain. MRI revealed a large area of bone marrow oedema without a zone of demarcation or subchondral fracture with a demonstration of shifting marrow oedema on the follow-up MRI scan from the medial femur condyl to the tibia plateau lateral and then to the distal tibia epiphysis. Treatment with the bisphosphonate ibandronate, however, was unsuccessful. RMO is characterized clinically by migrating arthralgia of the weight-bearing joints of the lower limbs, mainly in middle-aged males. Although the aetiology is unknown, the pathophysiology of RMO seems to be closely related to transient osteoporosis of the hip (TOH), which has been considered a reversible stage of avascular necrosis of the hip (AVN). There is no causal treatment for RMO. Avoidance of weight bearing and use of analgesics are effective in reducing symptoms. The combination of RMO and AS yielded diagnostic difficulties, as the clinical picture and the marrow oedema seen on MRI could be attributed to several AS-related causes such as enthesitis, early stadium of arthritis, osteonecrosis, or sterile osteomyelitis.

[Fewer caesarean sections for breech presentation following external cephalic version according to a protocol in a special office visit]. / Minder keizersneden wegens stuitligging dankzij geprotocolleerde uitwendige versie in een speciaal spreekuur.

OBJECTIVE: Identification of determinants affecting the outcome of external cephalic version (ECV) in breech presentation, and investigation of the impact of ECV--performed according to a standardized protocol in an outpatient clinic--on the mode of delivery. DESIGN: Retrospective analysis. METHOD: In 2003 a standardized protocol of ECV was developed in the outpatient clinic for obstetrics of the Catharina Hospital in Eindhoven, the Netherlands; it was tested in 'version office visits'. Obstetric characteristics of all pregnant women who underwent attempts of ECV in the clinic from January 2004 until June 2006 during these sessions, and the subsequent births, were analysed. 85% of all ECVs were performed by the same hospital midwife and gynaecologist, in accordance with the protocol. RESULTS: ECV was successful in 96 of 209 pregnant women (46%). In 1 pregnant woman an emergency caesarean section was performed after ECV because of partial abruptio placentae. Nulliparity, incomplete breech presentation and low birth weight of the baby were associated with a lower success rate of ECV in this study. In the group with a successful ECV the percentage of caesarean deliveries was substantially lower (9 versus 83%; odds ratio: 0.21; 95% CI: 0.09-0.51). CONCLUSION: A regular team consisting of a hospital midwife and a gynaecologist working according to a standardized protocol for ECV in a case of breech presentation proved successful: the number of term breech presentations substantially diminished and therefore the percentage of caesarean sections was lower in the group in which ECV had been successful. This could have considerable impact on health care in the Netherlands in terms of reduced maternal morbidity and cost savings.

Second-line treatment in seronegative spondylarthropathies.

The literature concerning second-line treatment of seronegative spondylarethropathies from 1940 to August 1993 was reviewed. Sulfasalazine appeared to be effective in the treatment of ankylosing spondylitis (AS) and promising in reactive arthritis (ReA) and Reiters' syndrome (RS). Methotrexate and azathioprine were associated with a remarkable improvement in some cases of AS and RS. Methylprednisolone and levamisole were both efficacious in AS, but levamisole was associated with occasional severe side effects. Radiation therapy led to short-term improvement in AS, but was abandoned because of severe long-term side effects. Only sulfasalazine has been studied in sufficient detail to allow definitive conclusions, but methotrexate and azathioprine may be promising drugs.

A comparison of diflunisal and phenylbutazone in the treatment of ankylosing spondylitis.

A 12-week double-blind randomized drug trial followed by an open extension period of 36 weeks was carried out in 38 male patients with ankylosing spondylitis (AS) to compare the efficacy and safety of diflunisal (500 mg twice daily) and phenylbutazone (200 mg twice daily). Both drugs proved to be effective in improving the severity of symptoms associated with AS, and this improvement was maintained throughout the open extension period. Initially diflunisal had a more pronounced and rapid analgesic action, whereas phenylbutazone was more effective in increasing axial mobility. During the study 9 patients dropped out: 3 in each treatment group due to side effects and 1 in each group due to lack of efficacy; another patient was lost to follow-up. The two drugs were similarly safe as judged by the occurrence of adverse clinical effects, mainly gastrointestinal. This study again demonstrates the value of phenylbutazone in AS but, taking into account the possible haematological side effects, the use of other NSAIDs is stressed. Diflunisal is an alternative capable of improving the painful stiffness associated with AS.

Polychondritis and rheumatoid arthritis. Case report and review of the literature.

We present the case history of a 50-year-old man with seropositive erosive rheumatoid arthritis of 30-years standing who developed polychondritis simultaneously with several extra-articular rheumatoid manifestations, such as anaemia, subcutaneous nodules, pericarditis and episcleritis. The relevant literature is reviewed. Gradually, all symptoms and signs disappeared after start of treatment with 30 mg prednisone and 100 mg azathioprine daily. We suggest that the polychondritis in this patient was also an extra-articular manifestation of rheumatoid arthritis.

The moderate intestinal side effects of auranofin do not require prophylactic therapy with a bulkforming agent. Dutch Ridaura Study Group.

Incidences of diarrhoea and loose stools are reported up to 50% in patients starting treatment with auranofin. Moreover, +/-4% of patients discontinue treatment because of severe diarrhoea. We investigated whether a water binding agent would diminish the incidence of loose stools and diarrhoea. Endpoints were the patient's general impression of the quality of stools and a daily assessment of stool's frequency/consistency and adverse events. Secondly, some disease activity parameters were used to evaluate whether the bulkforming agent influences the efficacy of auranofin. In this study 269 patients suffering from Rheumatoid Arthritis (RA) were treated with auranofin 6 mgr daily for a period of six months. Simultaneously the patients were randomly treated with either a bulkforming agent (Volcolon: psyllium fibres) or placebo. Results show a 15% incidence of loose stools and diarrhoea during treatment with auranofin. During the treatment period the patients' general impression of defecation consistency showed a shift to softer types. The changes in defecation consistency was not significantly different between groups (Intention-to-treat analysis: C2=4.01; p=0.13). Also, the percentage of patients experiencing episodes of diarrhoea (reported as an adverse experience) was not different (14% of the patients treated with bulkformer versus 15% with placebo). During the first month 7% (n=5) of placebo treated patients reported short episodes of watery stools versus none in the bulkformer treated group. The percentage of days with loose or watery stools, reported on the diary cards, was consistently lower in bulkformer treated patients. Both groups improved equally with respect to disease activity parameters. Sixty-eight percent of patients continued auranofin treatment after the study period. In conclusion, these data do not support adjuvant therapy with a bulkforming agent on initiation of auranofin therapy. The overall low incidence of loose stools and diarrhoea suggests that a dose increase to 9 mgr daily is an option to enhance the efficacy of auranofin treatment.

Observational study on efficacy, safety, and drug survival of anakinra in rheumatoid arthritis patients in clinical practice.

BACKGROUND: The efficacy and safety of anakinra, a recombinant human interleukin 1 (IL1) receptor antagonist used in rheumatoid arthritis, has been documented in five randomised controlled studies. However, long term post-marketing efficacy data are lacking. OBJECTIVE: To evaluate the efficacy, safety, and drug survival of anakinra in clinical practice. METHODS: All patients with rheumatoid arthritis who started anakinra in six hospitals between May 2002 and February 2004 were included in a two year prospective, in part retrospective, cohort study. Efficacy was assessed using the 28 joint disease activity score (DAS28) and the EULAR response criteria. Safety was evaluated using the common toxicity criteria. Drug survival and prognostic factors were analysed using Kaplan-Meier and Cox proportional hazard analyses. RESULTS: After three months, 55% of the patients (n = 146) showed a response (43% moderate, 12% good). A subset of patients continuing anakinra after 18 months had a sustained clinical response compared with patients who switched to other disease modifying antirheumatic drug treatment (DAS28 improvement, 2.46 v 1.79). Drug survival was 78%, 54%, and 14% after three, six, and 24 months, respectively. The reason for discontinuation was lack of efficacy in 78% and adverse events in 22%. Except for higher drug survival in women (odds ratio = 0.51, 95% confidence interval, 0.27 to 0.97), no prognostic factors were found. Adverse events were reported 206 times in 111 patients, the most common being injection site reactions (36%). Serious adverse events occurred in 12% of the patients, with one classified as related. CONCLUSIONS: The short term efficacy and safety profile of anakinra are comparable to those found in randomised clinical studies. However, the drug survival of anakinra after two years is low, mostly because of lack of efficacy.

Assessment of outcome in ankylosing spondylitis: an extended radiographic scoring system.

OBJECTIVE: To develop and validate an extensive radiographic scoring system for ankylosing spondylitis (AS). METHODS: The Stoke Ankylosing Spondylitis Spinal Score (SASSS) was modified by adding a score for the cervical spine and defining squaring. This modified SASSS (mSASSS) is the sum of the lumbar and cervical spine score (range 0-72). 370 lateral views of the lumbar and cervical spine were used for development of the mSASSS, standardisation of observers, and for studying reliability. In a 48 week NSAID study of 57 patients, change over time and construct validity were studied. RESULTS: Interobserver correlations of the lumbar and cervical spine scores were good (r>0.95). The interobserver duplicate error was 0.55 in a range from 0 to 36. The mean change in the cervical and lumbar spine scores between weeks 0 and 48 of all patients was 1.45 (range 0-6.0) and 1.06 (0-5.0), respectively (paired t testing, p<0.001). Change in radiological score was seen in 36/57 (63%) patients (lumbar and cervical spine 11, cervical spine 12, lumbar spine 13 patients). CONCLUSION: The mSASSS is useful for assessing extensive radiographic damage in AS. It is reliable, detects changes over 48 weeks, and shows a satisfactory face and construct validity.

Specimen handling in an HPLC determination of phenylbutazone and its major metabolites in plasma, avoiding degradation of the compounds.

A problem usually not taken into account when a quantitative HPLC method for phenylbutazone is developed is the degradation of this drug and its metabolites not only upon storage, but also on extraction under acidic conditions, especially when the temperature is raised. Moreover, the degradation products in the chromatograms may interfere with the determination of gammahydroxyphenylbutazone. In our newly developed HPLC method, using feprazone as an internal standard, extreme care is taken to avoid degradation of the compounds during the extraction procedure. In view of the present results it is concluded that previously published data on phenylbutazone, oxyphenbutazone and gammahydroxyphenylbutazone levels should be considered with reserve.

IgA serum levels and disease activity in ankylosing spondylitis: a prospective study.

We investigated the possible association between serum IgA, IgM, and IgG and disease activity in a longitudinal study of 48 weeks' duration in 38 male patients with active ankylosing spondylitis receiving regular treatment with either phenylbutazone or diflunisal. Throughout the study serum IgA levels correlated most frequently with chest expansion and lumbar flexion index, and patients with extensive radiological changes also had the highest serum IgA levels. Likewise, changes in IgA, but not in IgM and IgG, correlated with changes in a composite index of disease activity (IDA). Changes in erythrocyte sedimentation rate (ESR) showed a similar correlation with changes in IDA, whereas changes in serum IgA and ESR showed no consistent correlation, suggesting that both parameters reflect different aspects of disease. Serum IgA, ESR, and IDA values all decreased during regular drug treatment, suggesting a disease modifying effect of the non-steroidal anti-inflammatory drugs (NSAIDs) studied. Regular measurement of serum IgA may be useful in the assessment of disease activity of ankylosing spondylitis.

Methotrexate in severe ankylosing spondylitis: an open study.

OBJECTIVE: To study the efficacy and toxicity of methotrexate (MTX) for patients with ankylosing spondylitis (AS) in a 36 week, open, single observer study. METHODS: Patients were selected for study if they had evidence of active disease and had failed to respond to treatment with nonsteroidal antiinflammatory drugs (NSAID) and sulfasalazine. Eleven patients entered the study, and 9 were evaluated at the end. Oral MTX (7.5-15 mg weekly) was given for at least 24 weeks; NSAID were kept at a stable dose. Efficacy was evaluated by calculating the relative difference of assessed variable between Week 0 and 24 and by patient evaluation. RESULTS: Assessed variables showed good relative improvement. Four patients decided to continue MTX; 3 used a lower dose of NSAID; one stopped NSAID: Five patient patients discontinued MTX: 3 of these had disease flares and restarted MTX. Side effects were mild and reversible. CONCLUSION: Results of our study showed that the majority of our patients with AS taking MTX had beneficial effects.

Pharmacokinetics of naproxen at two dosage regimens in healthy volunteers.

The pharmacokinetic differences between two dosage regimens of naproxen (1000 mg once daily vs 500 mg twice daily) were studied at steady-state in seven healthy male volunteers. The twice daily regimen resulted in statistically significant higher trough serum levels, larger AUC0----24; also the time span with a concentration over 50 micrograms/ml was longer. The urinary excretion of naproxen metabolites was slightly greater upon once daily dosing. The VDextrap and, to a lesser extent the total body clearance, were larger upon the once daily regimen with a longer t1/2 beta as a consequence. As yet one can only speculate about the therapeutic implications of these findings.

Lung function in patients with ankylosing spondylitis. A study of the influence of disease activity and treatment with nonsteroidal antiinflammatory drugs.

Progressive ankylosis of the thoracic skeleton in ankylosing spondylitis (AS) causes restrictive pulmonary function impairment characterized by a reduction in vital capacity (VC). After a wash-out period of 2 weeks, 33 men with active AS were treated with either diflunisal or phenylbutazone according to a double blind randomized design for 12 weeks, followed by an open extension period of 36 weeks. A spirometric study was performed at baseline, Week 12, and Week 48. In the active phase of the disease a correlation was found between VC and chest expansion, whereas neither of these variables was related to the thoracic pain and over-all disease activity. We also found that the VC correlated with the lumbar flexion index, but not with the erythrocyte sedimentation rate or IgA. Although all clinical efficacy variables showed an improvement during treatment with both drugs, no change in VC was found, even in patients with the most restricted ventilatory impairment. We conclude that the VC is not an appropriate variable for the evaluation of short term therapy in AS.

Pseudoporphyria due to naproxen. A cluster of 3 cases.

Pseudoporphyria is a photo-induced blistering disorder with increased skin fragility, caused among others by nonsteroidal antiinflammatory drugs. Lesions heal with scarring and milia. Porphyrin screen studies are normal in this disease. Histology and immunofluorescence resembles porphyria cutanea tarda. In this report we describe a cluster of three cases of naproxen-induced pseudoporphyria, and review briefly previously reported cases induced by naproxen. The majority of reported cases involve children. Physicians should be aware of this reversible skin disorder.

Treatment of pigmented villonodular synovitis of the knee with yttrium-90 silicate: prospective evaluations by arthroscopy, histology, and 99mTc pertechnetate uptake measurements.

The diffuse form of pigmented villonodular synovitis of eight knee joints of eight patients was treated by intra-articular injection of 185 MBq yttrium-90 silicate (90Y). Six patients had a recurrence of disease after one or two surgical synovectomies. After treatment with 90Y once or twice four knees showed clinical improvement with an accompanying decrease of the inflammatory activity as measured by the technetium-99m pertechnetate (99mTcO4-) uptake ratio and the severity of the diseased synovial tissue. Arthroscopy was performed before and six months after each 90Y treatment. The ratio of 99mTcO4- uptake in the inflamed compared with the normal knee joint correlated well with the macroscopical grading of pigmented villonodular synovitis. In all cases areas of persistent synovitis were found after the 90Y injection and this was confirmed both by histological examination and 99mTcO4- uptake measurements. Biopsy specimens taken from the diseased synovial areas showed histologically mostly less prominent and less numerous villi. The cartilage damage was slightly increased in only two cases. No radiological deterioration was found during follow up (mean 24 months, range 12-41). No complications of the radiosynoviortheses were noted.

A Dutch version of the functional index for ankylosing spondylitis: development and validation in a long-term study.

A Dutch Functional Index (DFI) for AS has been developed, containing 37 questions in essence this is a modification of a French index with additional questions. Internal consistency, reproducibility, criterion and construct validity and sensitivity to change were studied in different groups of AS patients. In a group of 149 patients the questionnaire was completed and internal consistency calculated (Cronbach's alpha = 0.94) after exclusion of three items. Reproducibility was studied in 39 patients with stable disease; Pearson correlation was 0.94. Criterion validity, against a 'gold standard' i.e. experts' observation of 25 items, was studied in 19 patients; r = 0.85. In a 48-week NSAID study patients were enrolled after a washout period: DFI scores before and after treatment showed significant improvement (P < 0.02). There were 187 DFI with corresponding clinical measurements, correlations varied from -0.30 to 0.68. Estimated measurement-remeasurement correlation was 0.87. The DFI is, thus, a potentially useful instrument, which is valid, reliable and sensitive to the effects of NSAID treatment.

Disease activity in ankylosing spondylitis: selection of a core set of variables and a first set in the development of a disease activity score.

A large number of variables are available for the assessment of disease activity in ankylosing spondylitis (AS). The aim of this study was to evaluate the validity of commonly used variables, to select a core set of valid variables for disease activity and finally to compute an AS disease activity score (AS-DAS). Data from two longitudinal studies were used. Principal component analysis and reliability analysis resulted in 11 factors: cervical mobility, lumbar flexion, subjective complaints, functional index (FI), enthesis index (EI), inflammatory response, IgA, IgM, root joints, swollen joints and spinal mobility. Based on discriminating power, reproducibility and correlation with disease duration, seven single variables were selected. In a subsequent discriminant analysis, an AS-DAS was computed of five variables, i.e. subjective complaints, FI, EI, root joints and C-reactive protein, which should be validated in the future. A core set of process variables solves the problem of multiple testing in clinical trials, and improves comparability.

Naproxen pharmacokinetics in patients with rheumatoid arthritis during active polyarticular inflammation.

Patients with rheumatoid arthritis often have hypoalbuminaemia as a sign of disease activity. In view of the extensive binding of naproxen to albumin, the pharmacokinetics of total and unbound drug were studied in eight patients and eight healthy male volunteers during chronic intake of 500 mg twice daily. The area under the serum concentration-time curve of total naproxen during a dose interval, AUC (0,12), smaller in patients (641 +/- 101 mg l-1 h) than in volunteers (896 +/- 85 mg l-1 h; P less than 0.0001). The unbound naproxen AUCu (0,12) was larger in patients (1.9 +/- 0.9 mg l-1 h) than in volunteers (0.7 +/- 0.2 mg l-1 h; P less than 0.01). The higher unbound naproxen concentrations in patients were accompanied by an approximately 40% increase in apparent clearance/bioavailability (CL/F) and a 60% increase in volume of distribution (V/F). Both CL/F and V/F were inversely correlated with the individual serum albumin concentration (r = 0.76, P less than 0.001; r = -0.85, P less than 0.001, respectively). The high unbound naproxen concentration in the serum of patients with active rheumatoid arthritis and concomitant hypoalbuminaemia is not known to be accompanied by an increase in side effects and may be beneficial if anti-inflammatory effects correlate with unbound drug concentration.

Sulfasalazine in the treatment of juvenile chronic arthritis: a randomized, double-blind, placebo-controlled, multicenter study. Dutch Juvenile Chronic Arthritis Study Group.

OBJECTIVE: To assess the efficacy, tolerability, and safety of sulfasalazine (SSZ) in the treatment of juvenile chronic arthritis (JCA). METHODS: We conducted a 24-week randomized, placebo-controlled, double-blind, multicenter study of patients with active JCA of both oligoarticular and polyarticular onset. Patients were treated with a dosage of 50 mg/kg/day of SSZ (maximum 2,000 mg/day) or placebo. The efficacy variables were joint scores, physician's, parents', and patient's overall assessments, and laboratory parameters of inflammation. RESULTS: Of the 69 patients enrolled, 52 (75%) completed the trial. Six patients (18%) withdrew from the placebo group, and 11 (31%) withdrew from the SSZ group (P = 0.18). In the intention-to-treat analysis of end point efficacy, between-group differences were significant for the overall articular severity score (P = 0.02), all global assessments (P = 0.01), and the laboratory parameters (P < 0.001). Adverse events occurred more frequently in the SSZ group and were the main reason for withdrawal (P < 0.001), but in all instances, these events were transient or reversible upon cessation of treatment. CONCLUSION: The results of this first placebo-controlled study show that SSZ is effective and safe in the treatment of children with oligoarticular- and polyarticular-onset JCA, although it was not well tolerated in one-third of the patients.

Effects of sulfasalazine treatment on serum immunoglobulin levels in children with juvenile chronic arthritis.

This article describes the effects of sulfasalazine (SSZ) treatment on serum immunoglobulin (Ig) levels in 6 children with oligoarticular- or polyarticular onset juvenile chronic arthritis (JCA). None of the children who developed dysimmunoglobulinemia during treatment showed clinical symptoms of this adverse event, in particular none developed severe infections. All patients regained normal immunoglobulin levels after discontinuing SSZ treatment. One patient with a partial IgA deficiency at the start of SSZ treatment showed a slow increase in the IgA level during treatment. During follow-up (4-6 years), one patient spontaneously developed a dysimmunoglobulinemia and one patient developed diabetes mellitus. Based on these case reports and review of the literature we advocate monitoring of serum immunoglobulin levels while on SSZ treatment.