The B. Shine Department of Rheumatology, Rambam Medical Center and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
SIR, The long-term remission (624 months) of refractory Wegener's granulomatosis seen following 46 infusions of infliximab (anti-TNF) therapy [1] compelled us to consider the following explanations. After an initial phase of therapy at 0-, 2- and 4-week intervals, infliximab is usually given every 8 weeks in order to prevent a decrease of effective antibody titre [2]. The remission of refractory and aggressive forms of Wegener's granulomatosis described in the article [1] continued for a much longer period. We propose that this effect may be the result of at least three factors.
First, the new maintenance regimes such as azathioprine, methotrexate, mycophenolate mofetil, leflunomide and azathioprine for patients 1, 2, 4, 5, and 6, respectively, were more effective than prior regimes.
Second, corticosteroid therapy along with infliximab infusion was given in much higher doses (35 mg/kg per day) than the corticosteroid dose (1 mg/kg per day) of a standard cyclophosphamidecorticosteroid course. That may have promoted the induction of remission and thereby explain long-term remission in patient 3 who received a high-dose corticosteroid course (80250 mg/day) for 6 months, and in whom infliximab was discontinued owing to suspected infection.
Third, we suggest another factor may be responsible. Aggressive forms of Wegener's granulomatosis, which were refractory to standard and intensified therapy, may be due to the existence of an autonomous vicious cycle cascade of TNF- production [3]. This may be substantiated by a signal transmission with the NF
B pathway [4]. We propose that TNF-family gene expression may be resistant to immunosuppressive therapy, and only TNF blockade may be capable of disrupting the vicious cycle cascade.
Similar resistance to therapy due to similar vicious cycles may occur in other conditions and directed anti-cycle therapy should be considered in these instances. So far a number of vicious cycle pathological processes has been reported. Re-entry cycle pathways in arrhythmia are known in cardiology. A vicious cycle in synovial chondromatosis node formation has recently been reported [5]. Immune complex-stimulated mononuclear and type 2 cytokines (interleukin 10, IL-6) create a vicious cycle that may help to maintain B-cell hyperactivity in systemic lupus erythematosus [6]. A vicious cycle in which TNF- and nitric oxide mutually provoked each other's production has been described in experimental autoimmune encephalomyelitis [7]. The interactions between T-cell-mediated immunity and epidermal keratinocytes and neutrophils form inflammation-boosting loops in psoriatic lesions [8]. A vicious cycle for the progression of IgA nephropathy might ensue in the proteinuric state [9]. Excessive HLA class II expression is found on the target tissues of the majority of human autoimmune diseases together with activated (IL-2 receptor-expressing) T lymphocytes, suggesting that the target tissues act as antigen-presenting cells for infiltrating autoreactive cells, which in turn produce molecules that maintain class II expression. This vicious cycle has been shown to operate in Graves' thyroiditis, in which interferon-
induces class II expression on thyrocytes, and thyrocytes expressing class II antigens present their autoantigens to T cells cloned from thyroid tissues affected by Graves' disease [10]. New approaches such as anti-TNF therapy may therefore be effective in the control of vicious cycle pathological conditions.
Notes
Correspondence to: A. Rozin, The B. Shine Department of Rheumatology, Rambam Medical Center, P.O. Box 9602, Haifa 31096, Israel. E-mail: a_rozin{at}rambam.health.gov.il
References
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