Potential for methotrexate exposure through contamination during parenteral use as an immunosuppressant.

BACKGROUND: To evaluate whether the risk of methotrexate (MTX) exposure through skin contamination using parenteral doses of 25 mg warrants special oncology handling precautions during administration. METHODS: We conducted a study with six human volunteers deliberately exposed to an entire dose of 25 mg MTX solution on their skin for 30 min. Serum levels of MTX were measured at baseline, 2, 4, 8, 12 and 24 h as well as serum homocysteine at baseline and 24 h after clinical exposure. Twenty-four-hour urinary excretion of MTX and possible local or systemic signs of toxicity were also recorded. RESULTS: All MTX serum concentrations were less than 0.02 micromol/L within the 24-h period. This is 500 times below the recommended serum concentration for which folinic acid supplementation is recommended. There was also no significant increase in homocysteine level to suggest MTX toxicity. The only adverse effects were mild local dermal reactions in three female volunteers. CONCLUSION: Deliberate skin contamination and possible inhalation of a 25 mg MTX solution failed to show significant or quantifiable serum and urine concentrations to suggest MTX toxicity. Precautions to prevent contact with MTX designed for oncology protocols are unnecessary for our rheumatology patients or their carers using these much lower immunosuppressant doses for autoimmune diseases.

Infliximab in severe active ankylosing spondylitis with spinal ankylosis.

BACKGROUND: Infliximab is an anti-tumour necrosis factor monoclonal antibody, which significantly improves pain, stiffness and functional disability outcomes in patients with active ankylosing spondylitis. There are limited data available on the efficacy of this treatment for the subgroup with established spinal ankylosis. AIM: To compare the treatment response of infliximab in active severe ankylosing spondylitis for patients with and without radiographic evidence of spinal ankylosis in the clinical practice setting. METHODS: Twenty-seven patients with mean Bath Ankylosing Spondylitis Disease Activity Index of 8.7, all HLA-B27 positive, with 11 (41%) having spinal ankylosis, were studied for 54 weeks. The qualification for initial and ongoing infliximab treatment was defined by the Australian Pharmaceutical Benefit Schedule (PBS), and 5 mg/kg of infliximab was given at 0 week (baseline), repeated at 2 and 6 weeks and every 6 weeks thereafter. At each time point, PBS-mandated and international consensus response measures were completed. Disease activity and outcome measures for spinal ankylosis subgroup and those who did not have spinal ankylosis were cross-sectionally compared at baseline and 1 year. RESULTS: Patients with spinal ankylosis tended to be older (P = 0.01). Although the subgroup with spinal ankylosis had higher baseline activity scores, the only significant difference between the subgroups was the degree of morning stiffness (P = 0.04). By 54 weeks, all patients including the subgroup with spinal ankylosis fulfilled the PBS criteria for continuation of treatment. Majority of patients including the subgroup with spinal ankylosis achieved the various international consensus response measures. Patients with spinal ankylosis also experienced significant improvements in health-related quality of life, with majority returning to full-time employment by 1 year. CONCLUSION: In real-life clinical practice, patients with established disease with spinal ankylosis and high levels of inflammation and disease activity can achieve a major clinical response with infliximab.

Etanercept in severe active rheumatoid arthritis: first Australian experience.

BACKGROUND: Etanercept reduces disease activity in adults with chronic rheumatoid arthritis (RA) who are resistant to other therapies. Medicare Australia Pharmaceutical Benefit Scheme subsidized treatment (since August 2003) restricts etanercept availability to a most drug-resistant RA population. The aim of the study was to assess the efficacy of etanercept in this unique group after 12 months of therapy. METHODS: A prospective study of the first 50 consecutive private practice, adult RA patients whom were commenced on etanercept. The primary efficacy measures included short form 36 scores, Disease Activity Score 28, American College of Rheumatology (ACR) response improvement in per cent and the ACR individual core set components at baseline, 3 and 12 months. Analysis was by intention to treat. RESULTS: There was significant improvement in all mean short form 36 component scores (P < 0.05) and all ACR core set component scores (P < 0.05) comparing 12 months to baseline. The disease activity score 28 also significantly fell from baseline at both 3 and 12 months (P < 0.05). The ACR 20% response significantly improved (P < 0.05) both at baseline to 3 months 92% (81.2, 96.9) and to 12 months 80% (67.0, 88.8). Serious adverse events occurred in 16%. At 12 months 88% completed treatment. CONCLUSION: Etanercept therapy will, by 3 and 12 months, significantly improve the short form 36, disease activity score 28, ACR 20% response and core set components. Our results are similar to international studies using etanercept in efficacy and tolerance despite our cohort being more resistant to preceding drug therapy. Etanercept offers this unique active severe refractory late RA Australian population a new therapeutic option to control their disease.

Autologous peripheral blood stem cell transplantation with in vivo T-cell depletion for life threatening refractory systemic lupus erythematosus.

We report the first Australian application of autologous haemopoietic stem cell transplantation in a 39-year old woman with severe systemic lupus erythematosus (SLE) and multiple life threatening complications, refractory to conventional therapy including intravenous cyclophosphamide. Our transplant technique, although not unique, differs from most published reports, in which an unmanipulated peripheral stem cell graft was used with in vivo lymphocyte depletion using rabbit antithymocyte globulin (ATG). Successful stem cell mobilization was achieved using granulocytecolony stimulating factor mobilization with methylprednisolone cover, after an initial attempt at mobilization was curtailed by respiratory arrest from upper airway obstruction due to cricoarytenoiditis, requiring tracheostomy. Conditioning regimen for the transplantation was cyclophosphamide 50 mg/kg on days -5 to -2 and rabbit ATG 2.2 mg/kg on days -3 and -2. An unmanipulated autograft was infused, with in vivo T-cell depletion achieved through a further dose of ATG given on day +2 postinfusion. The autologous transplant was well tolerated without fever or other serious complication. At 12 months follow-up post-transplantation, there is an objective evidence of near-complete response with SLE disease activity index scores falling from 40 pretransplant to 2. We conclude that HSCT with unmanipulated peripheral stem cell graft and in vivo lymphocyte depletion with ATG is safe and effective therapy for cyclophosphamide refractory SLE.

Etanercept treatment of renal amyloidosis complicating rheumatoid arthritis.

Rheumatoid arthritis and juvenile arthritis represent the commonest diseases complicated by AA amyloidosis in developed countries. Up to 5% of patients with rheumatoid arthritis will develop AA amyloidosis, with renal failure being the commonest cause of mortality. To date, treatment of this condition has focused on suppressing the underlying inflammatory condition with drugs such as cyclophosphamide and chlorambucil, but both these drugs are associated with myelotoxicity, leukaemia and sterility. Tumour necrosis factor-alpha (TNF-alpha) is thought to be involved in amyloid deposition. The efficacy of anti-TNF-alpha therapy (etanercept) in the treatment of renal amyloidosis complicating rheumatoid arthritis is demonstrated here and the current scientific data on this subject are presented.

Occurrence of (E)-4-hydroxy-2-nonenal in plasma and synovial fluid of patients with rheumatoid arthritis and osteoarthritis.

(E)-4-Hydroxy-2-nonenal (HNE), a cytotoxic propagation product of lipid peroxidation, is present in the synovial fluid (0.54 (0.19) mumol/l; mean (SE), n = 9) and plasma (0.34 (0.09) mumol/l, n = 9) of patients with rheumatoid arthritis. This compound was also found in the synovial fluid (0.24 (0.19) mumol/l, n = 9) and plasma (0.09 (0.03) mumol/l, n = 9) of patients with osteoarthritis. The concentration of HNE in the plasma of patients with rheumatoid arthritis was significantly greater than in patients with osteoarthritis.

Correlation between tests of muscle involvement and clinical muscle weakness in polymyositis and dermatomyositis.

A correlation study was performed on the degree of muscle weakness in 36 patients with dermatomyositis and 69 with polymyositis in relation to muscle biopsy findings, electromyography (EMG) abnormalities, and serum concentrations of creatine kinase (CK), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes. Statistically significant correlations were found between muscle weakness and EMG results in patients with polymyositis, and between muscle weakness and serum CK and AST levels in dermatomyositis. As expected, correlations were found between the results of the three enzyme determinations in both groups of patients.

Polydermatomyositis with anti-PL7 antibody: clinical and laboratory follow-up over a five year period.

Anti-PL7 antibodies to threonyl-tRNA synthetase purified from beef liver were observed in the serum of a dermatopolymyositis patient. They were identified by CIE and DID using a standard anti-PL7 antiserum and quantified by ELISA in serum samples taken over a five year period. The level of antibodies against not only threonyl-tRNA synthetase but also several muscle proteins including tropomyosin, was strongly correlated with disease activity and treatment. This correlation may prove important both in monitoring the response of the patient to treatment and to our understanding of the aetiology of the disease.

Rheumatoid arthritis and hereditary angioedema.

We describe a case in which rheumatoid arthritis (RA) developed in a patient with hereditary angioedema. Hereditary angioedema, one of the inherited complement deficiencies, has been reported in association with a number of autoimmune disorders, but there has been only 1 report of an association between RA and hereditary angioedema.

Improved detection of anti-Jo-1 antibody, a marker for myositis, using purified histidyl-tRNA synthetase.

The increased detection of anti-Jo-1 antibody afforded by the use of the purified antigen, histidyl-tRNA synthetase, in counterimmunoelectrophoresis is demonstrated. Using purified antigen, anti-Jo-1 antibody was detected in the sera of 16/33 (48.5%) patients with confirmed myositis and in 20/45 (44.5%) patients with confirmed or possible myositis. This rate is approximately double that obtained with commercial thymus extracts both in this study and seven others reported in the literature. The presence of antibody shows marked correlation with the activity of myositis at the time of serum sampling and with the presence of interstitial lung disease. Detection rates are similar in patients with polymyositis and dermatomyositis both with and without additional connective tissue diseases.

Dermatopolymyositis and other connective tissue diseases: a review of 105 cases.

Of 105 cases seen over 12 years with mean 4 years followup, there were 69 with polymyositis (PM) and 36 with dermatomyositis (DM). and in 43 this complicated another connective tissue disease (CTD). Primary PM had onset a decade later than others and most severe myopathy occurred in DM. Earliest symptoms were polyarthritis and Raynaud's phenomenon with frequent sicca syndrome (51%). The less than universal prevalence of elevated muscle enzymes (68%), myopathic electromyography (86%). and abnormal muscle biopsy (78%) emphasizes the need for complete evaluation in all cases. Improvement occurred in 69% overall, including all 23 given no therapy or low dose corticosteroids and 59% of the remainder who received high dose corticosteroids with added cytotoxics in one-quarter. Outcome was worse in older patients and in those where weakness exceeded 4 months before diagnosis. Eight of 19 deaths were due to myositis or its therapy which also caused considerable morbidity. Malignancy in 16 cases was temporally related to myositis in half of these cases.