Conversion of patients with rheumatoid arthritis from the conventional to a microemulsion formulation of cyclosporine: a double blind comparison to screen for differences in safety, efficacy, and pharmacokinetics.

OBJECTIVE: To assess whether patients with rheumatoid arthritis (RA) may be converted, on a milligram-to-milligram basis, from conventional cyclosporin A (CyA, Sandimmun) to the microemulsion formulation (Neoral) with maintenance of longterm safety, and to compare cyclosporin A (CyA) pharmacokinetics between formulations. METHODS: In this double blind, multicenter, parallel group study, 51 patients receiving stable conventional CyA maintenance treatment were randomized to continue conventional CyA (n = 27) or to convert to CyA microemulsion (n = 24) and were monitored for 52 weeks. Trough blood CyA levels were measured before and at intervals after conversion. CyA steady-state area under the curve was assessed one week before and 2 and 6 weeks after randomization in 15 patients in each treatment arm. CyA trough levels and pharmacokinetic results remained unknown to investigators throughout the study. CyA doses were titrated as necessary on the basis of clinical evaluation and disease activity assessments. RESULTS: Initial mean daily doses were 3.5 mg/kg/day (conventional CyA) and 3.3 mg/kg/day (CyA microemulsion) and did not change significantly during the study. The mean bioavailability of CyA from the microemulsion formulation was 23% higher than from conventional CyA. Replicate assessments indicated a more reproducible pharmacokinetic profile with CyA microemulsion. The overall incidence and nature of adverse events and changes in vital signs and laboratory variables were similar in both groups. No clinically relevant differences in efficacy were found between treatments. No loss of efficacy and no tolerability problems occurred after conversion from conventional to microemulsion CyA. CONCLUSION: Existing CyA dosing guidelines, formulated for conventional CyA, are suitable for longterm CyA microemulsion therapy of patients with RA. These results indicate the pharmacokinetic advantages of the microemulsion formulation.

Plastic bowing of the forearm in the more mature skeleton.

An 18 year old male suffered plastic bowing of both forearm bones following an industrial accident in which his forearm was caught by an electric hoist. Plastic bowing of both the radius and ulna occurred. This deformity, usually seen in children, was produced by an unusual set of circumstances, with a transverse force being applied for a considerable time. All four cases of 'adult' plastic bowing deformity have been the result of industrial accidents and were always the result of a transverse force acting upon the limb. Although, initially, after manipulation there was only minimal improvement in range of movement, progressive improvement was achieved with physiotherapy. In the present case early mobilization resulted in a good functional outcome for the patient.

Visual function and long-term chloroquine treatment.

Ophthalmic examinations and selected tests of visual function were performed on 64 patients with rheumatoid arthritis who had received daily doses of 200 mg chloroquine sulphate for periods ranging from 3 to 11 months. Visual fields were determined by Humphrey automated perimetry and Amsler grids and a further battery of four tests of macular function (visual evoked potentials, critical flicker fusion threshold, Cambridge contrast sensitivity and the macular dazzle test) were administered. No case of retinal pigmentary abnormalities plus visual loss was found, but 2 patients were advised to cease chloroquine therapy on the basis of funduscopic findings. A small group of patients with relatively poor scores on one or more tests had normal visual fields and ophthalmic findings. There were no significant partial correlations between test results and the cumulative dose of chloroquine. These results support the opinion that currently recommended doses of chloroquine pose a minimal risk of retinal toxicity.

Overuse ballet injury of the base of the second metatarsal. A diagnostic problem.

Performing classical ballet may cause major stress to the feet of the dancer. A variety of foot injuries have been described, with one such injury being an overuse syndrome involving the base of the second metatarsal and adjacent Lisfranc's joint. The diagnosis for this syndrome usually requires differentiating synovitis of Lisfranc's joint from a stress reaction of the base of the second metatarsal. Prompt diagnosis is important since the treatment for these two conditions differs significantly and, in the case of bone stress reaction, delay can cause progression of the lesion. We report good clinical results in a group of eight ballerinas for whom we obtained early diagnosis and treatment of their injuries. This is in contrast to poor results reported in the literature if the diagnosis and management of these types of injuries are delayed. We developed a simple diagnostic protocol to enable diagnosis at presentation. When a bone stress reaction had progressed to a fracture line, a characteristic appearance was found on magnetic resonance imaging, suggesting a specific mechanism of injury. A possible mechanism for this injury is discussed.

Regeneration of the semitendinosus and gracilis tendons following their transection for repair of the anterior cruciate ligament.

Apparent regeneration of the tendons of the semitendinosus and gracilis muscles after their use for anterior cruciate ligament reconstruction was noted during routine follow-up of 225 patients. From this group, four patients were selected for thorough examination, including magnetic resonance imaging, electromyographic studies, strength testing, and clinical examination. The results demonstrate that these tendons appear to regrow and are probably functional.

Osteochondral fractures of the dome of the talus.

Twenty-four patients who had an osteochondral fracture of the dome of the talus were examined by plain radiography, magnetic resonance imaging, computerized tomography, and, when indicated, scintigraphy. When plain radiographs of the ankle are relied on for the diagnosis of an osteochondral fracture of the talus, many lesions remain undiagnosed. Stage-I osteochondral fractures show no diagnostic changes on plain radiographs, and Stage-II lesions are usually subtle and, therefore, are often overlooked by both radiologists and clinicians. The use of scintigraphy as a screening procedure and of magnetic resonance imaging for patients who have positive scintiscans showed that osteochondral fractures are more common than has previously been indicated in the literature. Scintigraphy should be used to assess patients when there is clinical suspicion of an osteochondral fracture but the plain radiographs appear to be negative. Patients who have positive scintiscans should be assessed by magnetic resonance imaging. Patients who have abnormal plain radiographs will derive no major benefits from magnetic resonance imaging; for all but one of these patients, computerized tomography was adequate for staging the fracture.

Clofazimine-mediated enhancement of reactive oxidant production by human phagocytes as a possible therapeutic mechanism.

Clofazimine, at concentrations within the therapeutic range (0.01-5 micrograms/ml), stimulated human polymorphonuclear leucocytes (PMNL) to generate increased amounts of reactive oxidants (RO) when activated with the tripeptide leucoattractant N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP), calcium ionophore, phorbol myristate acetate and opsonised zymosan. Clofazimine per se did not activate the membrane-associated oxidative metabolism of PMNL, but rather primed these cells to hyperreact to the various stimuli. To investigate the therapeutic significance of these observations clofazimine was administered to patients with various chronic inflammatory diseases (lichen planus, discoid lupus erythematosus and rheumatoid arthritis) and generation of RO by FMLP-activated phagocytes was measured before and during clofazimine administration. A statistically significant potentiation of RO generation by FMLP-activated phagocytes was observed during clofazimine administration. Since RO are immunosuppressive and antimicrobial the therapeutic mechanisms of clofazimine may be related to pro-oxidative interactions of this agent with phagocytes.

The antirheumatic effect of benoxaprofen.

This study was undertaken to investigate the antirheumatic activity of the non-steroidal anti-inflammatory drug benoxaprofen. Ten patients with definite or classic rheumatoid arthritis were assessed before beginning drug therapy, using standard clinical criteria and serological tests of disease activity. These tests were repeated monthly during treatment with benoxaprofen for a period of 6 months. The results showed that benoxaprofen improved clinical parameters of disease activity, including morning stiffness, walking time, tenderness and swelling of joints and pain rating, in 7 of the 10 patients studied. One patient's condition remained unchanged and 2 deteriorated during the trial period. In the group of 7 patients who showed clinical improvement there were significant reductions in serum levels of rheumatoid factor, C-reactive protein, alpha 1-antitrypsin, IgA, IgM and IgE, as well as in erythrocyte sedimentation rates. Five of the 10 patients, all of whom were initially seropositive for rheumatoid factor, became seronegative at the end of the trial and 5 of 6 with raised C-reactive protein levels registered undetectable levels. Although this trial was uncontrolled, these findings indicate that benoxaprofen has antirheumatic properties.

Immunological assessment of patients with rheumatoid arthritis--evaluation of the effects of propranolol.

Some humoral and cellular immune functions were evaluated in a group of 10 patients with rheumatoid arthritis before and after 3 months of treatment with the beta-blocking agent propranolol. Humoral parameters measured were serum immunoglobulins including IgE, auto-antibodies, C-reactive protein, total haemolytic complement activity and the complement components C3 and C4. Cellular functions assessed were polymorphonuclear leucocyte chemotaxis, phagocytosis and postphagocytic nitroblue tetrazolium reduction, hexose monophosphate shunt activity and myeloperoxidase-mediated iodination of ingested protein; lymphocyte transformation to the mitogens phytohaemagglutinin and concanavalin A was also investigated. No alteration of humoral factors and neutrophil functions was observed following propranolol administration (40 mg 3 times a day), but lymphocyte transformation was significantly increased. Improved lymphocyte function did not correlate with clinical improvement.

The heart in rheumatoid arthritis: an echocardiographic study.

An echocardiographic study of 44 patients with active rheumatoid arthritis was carried out by means of a Picker ultrasonic laminograph. A posterior pericardial effusion was found in 14 patients (32%) and pericardial thickening in 5 (11%). The maximum amplitude of the anterior cusp of the mitral valve was reduced in 18 patients, and the diastolic (EF) slope was abnormal in 17 patients. The posterior cusp movement and left ventricle diameter were normal. The over-all incidence of cardiac involvement in these patients was 73%. The incidence of heart abnormalities given by echocardiographic diagnosis of cardiac manifestation of rehumatoid arthritis correlates well with the incidence derived from postmortem studies.

Pernicious anaemia with hypogamma-globulinaemia. A case report.

Auto-immune mechanisms are important in the evolution of pernicious anaemia, but cannot be demonstrated in all cases. Cell-mediated immunity is involved in the pathogenesis, and explains the occurrence of pernicious anaemia in patients with hypogammaglobulinaemia. The pernicious anaemia seen in these patients differs in some respects from the classical form of the disease. The case history of a patient with pernicious anaemia and hypogammaglobulinaemia is presented, and the possible pathological mechanisms are discussed.

Gold therapy in rheumatoid arthritis.

Forty patients with active rheumatoid arthritis were treated with intramuscular injections of gold salts. A significant response was shown by 67,5% of the patients. Treatment was discontinued owing to side-effects in 35%. Dermatitis and proteinuria from renal damage were the commonest complications of treatment. The method of treatment and its side-effects are discussed.

Sporadic ulcero-osteolytic neuropathy in Blacks. A report of two cases.

The triad of a peripheral neuropathy, skin ulceration and destruction of bones and joints of the feet is called ulcero-osteolytic neuropathy, when other common causes of similar lesions have been excluded. Malnutrition, alcoholism and local trauma predispose to the development of the condition. It is to be differentiated from burnt-out leprosy, and is a chronic condition that eventually leads to characteristic deformities.

Pseudogout--CPPD arthropathy, Case reports.

Pseudogout, or calcium pyrophosphate arthropathy, is a crystalline synovitis, characterised either by acute attacks of joint pain, which usually occur in the large joints, or by a more chronic, progressive form of joint disease. The essential features of the disease are chondrocalcinosis and the presence of pyrophosphate crystals in the synovial fluid. The exact pathogenesis is unknown. Case reports of 2 patients with confiemed pseudogout, and of 1 who is suspected to be suffering from the disease, as well as a summary of the outstanding aspects of the condition, are presented.