response of treatment-resistant adult-onset Still's disease to thalidomide.
A 44-year-old woman with a 4-year history of adult-onset Still's disease required high doses of prednisolone to control 2-weekly attacks of fever associated with synovitis and a rash. Immunosuppressive agents (intravenous methylprenisolone, pulsed cyclophosphamide and immunoglobulins, methotrexate, azathioprine, colchicine, hydroxychloroquine, cyclosporin, mycophenolic acid, and hydroxyurea) failed to induce remission or enable a reduction in prednisolone below 30 mg daily. Azathioprine with pentoxyphylline was also tried without success.
Peripheral blood mononuclear cells (PBMC) from the patient and an age and sex-matched control were isolated and stained for intracellular cytokines. At this stage, the patient was taking azathioprine 150 mg daily, pentoxyphylline 400 mg three times daily, and prednisolone 30 mg daily. Half the cells were stimulated with ionomycin and phorbol myristate acetate (PMA) in order to induce cytokine production and incubated with Brefeldin A to inhibit protein export. Cell membranes were permeabilised with saponin to enable penetration of a phycoerythrin-conjugated monoclonal antibody recognising TNFa and analysed by fluorescence-activated-cell sorting (FACS). The percentage of unstimulated, TNFa-positive PBMC was greater in the patient compared with the control. The most marked difference was seen after in-vitro stimulation. In the controls, approximately 4.7% of PBMC stained positively for TNFa after stimulation (figure B) compared with approximately 42.7% of PBMC in the patient (figure D). On physical characteristics and surface staining with a monoclonal antibody recognising CD14 these cells were both monocytes and lymphocytes. Serum TNFa assayed by ELISA at the same time was undetectable.
Thalidomide has been shown selectively to inhibit TNFa production in stimulated human monocytes by enhancing TNFa mRNA degradation.1,2 After obtaining hospital drug committee approval and informed consent from the patient (who had previously undergone a hysterectomy) thalidomide was begun at 200 mg daily, tapering to 100 mg daily over 2 weeks. Pentoxyphylline was continued. There was marked clinical improvement and she remained free from symptoms for 6 months. Prednisolone was reduced to 7.5 mg daily within several weeks. A minor relapse followed withdrawal of pentoxyphylline. Thus, although this agent was not effective when combined with azathioprine, it may have contributed to thalidomide-induced suppression of TNFa.3 Monitoring of symptoms and nerve conduction studies continues and no features of peripheral neuropathy are apparent after 6 months of treatment with thalidomide. Repeat intra-cytoplasmic staining after the introduction of thalidomide showed that the proportion of TNFa-producing cells fell (figure F); 1.4% of cells produced TNFa, compared with approximately 42.7% of cells before treatment with thalidomide.
Thalidomide fell into disrepute because of its teratogenic potential and its association with axonal neuropathy, which may be irreversible. However, thalidomide has now been found to have immunosuppressive properties. In erythema nodosum leprosum, thalidomide reduces serum TNFa levels and dermal infiltration by polymorphonuclear cells, with rapid involution of nodules and resolution of systemic symptoms within 48 hours.4 Thalidomide inhibits viral replication in HIV-1 monocytoid cell cultures, most likely due to a reduction in TNFa production.5 It has an established role in the treatment of HIV-1-associated aphthous ulceration and also in graft-versus-host disease.2 There are reports of responses to thalidomide in Behcet's syndrome, pyoderma gangrenosum, sarcoidosis, rheumatoid arthritis, and discoid lupus erythematosus.1,2 There are no previous reports of the use of thalidomide in adult-onset Still's disease.
In our patient thalidomide was clinically effective in inducing and maintaining remission and symptomatic improvement correlated with a reduction in TNFa production by PBMC. Intracellular staining for cytokines may be more physiologically relevant than measuring serum levels of cytokines and may help with drug selection. It may also provide a clinically useful surrogate marker of disease activity in a variety of chronic, immunologically mediated disorders.
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