Iain Watt

Treatment of rheumatoid arthritis with recombinant human interleukin‐1 receptor antagonist

OBJECTIVE To evaluate the efficacy and safety of interleukin-1 receptor antagonist (IL-1Ra) in patients with rheumatoid arthritis (RA). METHODS Patients with active and severe RA (disease duration <8 years) were recruited into a 24-week, double-blind, randomized, placebo-controlled, multicenter study. Doses of nonsteroidal antiinflammatory drugs and/or oral corticosteroids (< or =10 mg prednisolone daily) remained constant throughout the study. Any disease-modifying antirheumatic drugs that were being administered were discontinued at least 6 weeks prior to enrollment. Patients were randomized to 1 of 4 treatment groups: placebo or a single, self-administered subcutaneous injection of IL-1Ra at a daily dose of 30 mg, 75 mg, or 150 mg. RESULTS A total of 472 patients were recruited. At enrollment, the mean age, sex ratio, disease duration, and percentage of patients with rheumatoid factor and erosions were similar in the 4 treatment groups. The clinical parameters of disease activity were similar in each treatment group and were consistent with active and severe RA. At 24 weeks, of the patients who received 150 mg/day IL-1Ra, 43% met the American College of Rheumatology criteria for response (the primary efficacy measure), 44% met the Paulus criteria, and statistically significant improvements were seen in the number of swollen joints, number of tender joints, investigators assessment of disease activity, patients assessment of disease activity, pain score on a visual analog scale, duration of morning stiffness, Health Assessment Questionnaire score, C-reactive protein level, and erythrocyte sedimentation rate. In addition, the rate of radiologic progression in the patients receiving IL-1Ra was significantly less than in the placebo group at 24 weeks, as evidenced by the Larsen score and the erosive joint count. IL-1Ra was well tolerated and no serious adverse events were observed. An injection-site reaction was the most frequently observed adverse event, and this resulted in a 5% rate of withdrawal from the study among those receiving IL-1Ra at 150 mg/day. CONCLUSION This study confirmed both the efficacy and the safety of IL-1Ra in a large cohort of patients with active and severe RA. IL-1Ra is the first biologic agent to demonstrate a beneficial effect on the rate of joint erosion.

A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: Radiologic progression and correlation of genant and larsen scores

OBJECTIVE To evaluate radiographic progression and the relationship of radiologic scores obtained by the Genant and Larsen methods in a clinical trial of recombinant human interleukin-1 receptor antagonist (IL-1Ra). METHODS Patients with rheumatoid arthritis (RA) were randomized into 4 groups: placebo (n = 121) or IL-1Ra at a daily dosage of 30 mg (n = 119), 75 mg (n = 116), or 150 mg (n = 116). Hand radiographs obtained at baseline, 24 weeks, and 48 weeks were scored using both methods. RESULTS At 24 weeks, by the Genant method, there was significant reduction in the score for progression of joint space narrowing (JSN) and the total score (a combination of erosion and JSN) in all treatment groups. Least-squares mean changes in the Genant erosion score from baseline to 24 weeks were significantly reduced after treatment with IL-1Ra at 30 mg/day and for all IL-1Ra treatment groups combined. The changes corresponded to a reduction of 38% in erosion, 58% in JSN, and 47% in total score. Patients treated with IL-1Ra at 75 mg/day had a significant reduction in the Larsen erosive joint count (LEJC), and all IL-1RA-treated groups combined showed a 45% reduction. Correlations (r) between the Genant total and Larsen scores were 0.84 at baseline, 0.83 at week 24, and 0.83 at week 48 (P < 0.0001); correlations between the Genant erosion score and the LEJC were 0.83 (P < 0.0001) at all visits; correlations between the Genant total and the Larsen scores were 0.32 and 0.49 (P < 0.0001) for progression from baseline to week 24 and from baseline to week 48, respectively; correlations between the Genant erosion score and the LEJC were 0.36 and 0.41 (P < 0.0001) for progression to weeks 24 and 48, respectively. CONCLUSION IL-1Ra reduced radiologic progression of RA. Scores by the 2 methods correlated strongly for each individual time point, but much less strongly for assessments of disease progression.

Computed tomography in pulmonary emphysema

Fifty-three patients with chronic obstructive airways disease and 19 age-matched controls were studied using computed tomography (CT). The study shows that CT can detect the presence and distribution of pulmonary emphysema. Pulmonary vascular changes detectable on chest radiography correlate well with lung density as measured by CT. Patients with marked CT changes of emphysema had significantly greater impairment of diffusion capacity and FEV1.0/VC than the patients with less severe changes.

Distinctive radiological features of small hand joints in rheumatoid arthritis and seronegative spondyloarthritis demonstrated by contrast-enhanced (Gd-DTPA) magnetic resonance imaging

A series of patients with clinically early inflammatory joint disease due to rheumatoid arthritis, psoriatic arthritis and Reiters syndrome were examined by plain film radiography and magnetic resonance imaging (MRI). The spin echo T1-weighted precontrast, T2-weighted, and, especially, T1-weighted postcontrast images demonstrated distinct differences in the distribution of inflamatory changes, both within and adjacent to involved small hand joints. Two major subtypes of inflammatory arthritis were shown, thus providing a specific differential diagnosis between rheumatoid arthritis and some patients with seronegative spondyloarthritis. In particular, all the patients with Reiters syndrome who were studied, and half of those with psoriatic arthritis, had a distinctive pattern of extra-articular disease involvement. The need for a new classification of clinical subsets in psoriatic arthritis has been recently suggested. The present findings suggest that magnetic resonance imaging could be useful in such a reclassification of seronegative spondyloarthritis, as well as offering considerable potential for a reappraisal of pathogenesis and therapy. In this series, it was also noted that juxta-articular osteoporosis on plain film did not correlate with bone marrow oedema on MRI. Hence the aetiology of this common radiographic finding also merits further consideration.

Arthropathies in palaeopathology: The basis of classification according to most probable cause

Abstract A scheme is presented for the classification of joint changes seen in skeletal material according to their most probable cause. One of the critical factors in making this classification is the description of the pattern of pathological changes noted in the skeleton. It is important to consider the skeleton in its entirety, and a valid classification cannot be made from the examination of single sets of joints or single elements of the skeleton. The description of the pathology of a skeleton should include an account of the joints which are present and examined, those which are normal, as well as those which are abnormal. The classification of lesions in palaeopathological material must be securely grounded in modern clinical practice if useful comparisons are to be made between series and disease in modern populations. If this is not the case, there is a serious danger of over-interpretation and over-simplification.

EULAR recommendations for calcium pyrophosphate deposition. Part II: Management

Objectives To develop evidence-based recommendations for management of calcium pyrophosphate deposition (CPPD). Methods A multidisciplinary guideline development group of 15 experts, representing 10 European countries, generated key propositions for management of CPPD using a Delphi consensus approach. For each recommendation research evidence was searched systematically. Whenever possible, the effect size and number needed to treat for efficacy and RR or OR for side effects were calculated for individual treatment modalities. Strength of recommendation was assessed by the European League Against Rheumatism visual analogue scale. Results Nine key recommendations were generated, including topics for general management, treatment of acute attacks, prophylaxis against recurrent acute attacks and management of chronic symptoms. It was recommended that optimal treatment requires both non-pharmacological and pharmacological treatments. For acute CPP crystal arthritis, cool packs, temporary rest and joint aspiration combined with steroid injection are often sufficient. For prophylaxis or chronic inflammatory arthritis with CPPD, oral non-steroidal anti-inflammatory drugs with gastroprotective treatment and/or low-dose colchicine 0.5–1.0 mg daily may be used. Other recommendations included parenteral or oral corticosteroid for acute CPP arthritis in those unresponsive or unsuited to other measures, and low-dose corticosteroid, methotrexate or hydroxychloroquine for chronic inflammatory arthritis with CPPD. Asymptomatic CPPD requires no treatment. Strength of recommendations varies from 79% to 95%. Conclusion Nine key recommendations for management of CPP crystal associated arthritis were developed using both research evidence and expert consensus. Strength of recommendations was provided to assist the application of these recommendations.

MAGNETIC RESONANCE IMAGING OF PATELLAR TENDONITIS

The radiological and MRI appearances of 24 knees with patellar tendonitis resistant to conservative therapy were analysed to identify the characteristic MRI appearance and to determine if the patellar morphology was abnormal. A significant thickening of the tendon was found in all cases; this was a more reliable diagnostic feature than a high signal within the superior posterior and central aspect of the tendon at its proximal attachment. The site of the lesion shown by MRI is more compatible with impingement of the inferior pole of the patella against the patellar tendon than a stress overload of the tendon. There were no significant differences in the length of the patella, inferior pole or length of the articular surface when the patellar morphology was compared with that of a matched control group.

Congenital coronary artery fistulae: six new cases with a collective review.

Primary congenital coronary artery fistula is diagnosed in two of every thousand patients investigated by angiocardiography. Males and females are equally affected and most frequently present under the age of 10 years. Fistulae originate from right and left coronary arteries in almost equal proportion but over 90% drain to the right side of the heart. Over half the patients present without symptoms but with a continuous murmur; as age increases so does the incidence of complications. Cardiac failure is the commonest complication. Three-quarters of patients presenting over the age of 40 have symptoms of cardiac failure. The clinical picture closely resembles that of patient ductus arteriosus but in a proportion of cases the physical signs and chest radiograph may suggest the diagnosis. A hitherto undescribed association of cardiac failure and a fistula from the left coronary artery to the left ventricle is reported. High-quality angiocardiography, preferably with selective coronary arteriography, is essential. Surgical correction carries a low mortality (2.2%) and is curative. The incidence of complications increases with age and prophylactic surgery is advocated before symptoms develop.

99mTc HMDP bone scanning in generalised nodal osteoarthritis. II. The four hour bone scan image predicts radiographic change.

In 14 patients with generalised nodal osteoarthritis a four hour bone scan image was found to predict the changes that occur on the radiograph at follow up between three and five years later. The scan abnormality appeared to precede the development of radiographic signs, and joints abnormal on scintigraphy showed most progression. Normal joints and joints abnormal on x ray alone showed little progression, and those that did subsequently alter became abnormal on scan. Scanning may provide a sensitive technique for monitoring osteoarthritis, it may enable a greater understanding of the underlying disease process, and allow evaluation of modifying therapeutic procedures.

Scintigraphic assessment of osteoarthritis of the knee joint.

Clinical, radiographic, and scintigraphic abnormalities of the knee joint have been correlated in a cross sectional study of 100 patients with osteoarthritis. The group comprised 73 women and 27 men with a mean age of 65.7 years. One hundred and ninety one of the 200 knees had clinical (175) or radiographic (185) evidence of osteoarthritis, or both (161). Scintigraphic images of the knees were obtained 4-5 minutes (early phase) and 2.5-3.5 hours (late phase) after intravenous injection of 600 mBq of technetium-99m diphosphonate. Abnormal images were recorded in 162 knees (81%), and six different patterns were detected. Generalised isotope retention around the knee (early or late phase) was less common than focal areas of uptake around the joint margin (early or late phase) or in the patella or subchondral bone (late phase). Some knees with abnormal scans were normal on radiography (n = 7), or vice versa (n = 21). Different scan patterns correlated with different clinical and radiographic features: the generalised pattern correlated with pain (odds ratio (OR) = 45.1) and osteophytes (OR = 48.3); joint line retention correlated with subchondral bone sclerosis on radiography (OR = 62.1); and subchondral bone retention correlated with more severe radiographic changes. It is concluded that different patterns of scintigraphic abnormality reflect various aspects of the disease process of osteoarthritis.