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[(tion. )17.7 (This mechanism, however)39.7 (, would not in itself explain)]TJ
0.02499 Tw 0 -1.2 TD
[(the development of )54.8 (ANA)-220.2 (or antibodies to ds-DNA.)]TJ
0.1149 Tw 1.2 -1.2 Td
(One further possible mechanism is the switch from the)Tj
-0.0088 Tw -1.2 -1.2 Td
[(predominant )17.7 (Th1 profile of )17.7 (T)-223.3 (lymphocyte response in RA)-186.4 (to)]TJ
0.0791 Tw T*
[(a )17.7 (Th2 response. RA)-274.4 (is characterized as a )17.6 (Th1 lymphocyte-)]TJ
0.1478 Tw T*
[(driven disease, the major )17.7 (T)-379.9 (cell cytokines involved being)]TJ
-0.0002 Tc 0 Tw T*
(TNF-)Tj
/T1_1 1 Tf
0 Tc [-0.2 (\002)]TJ
/T1_0 1 Tf
-0.00011 Tc 0.27969 Tw [0.1 (, interleukin \(IL\) 2, interferon-)]TJ
/T1_1 1 Tf
0 Tc 0 Tw [0.1 (\003)]TJ
/T1_0 1 Tf
-0.00011 Tc 0.27969 Tw [-0.1 (, and IL-12. )17.7 (Th2)]TJ
0.01199 Tw T*
(responses are associated with enhanced activity of IL-4, IL-)Tj
0.03999 Tw T*
(5, IL-6, IL-10, and IL-13, increased levels of which lead to)Tj
0.0125 Tc 0.3624 Tw T*
(upregulation of antibody production. Recent evidence)Tj
-0.00011 Tc -0.0107 Tw T*
[(suggests that SLE may itself be predominantly a )17.8 (Th2-driven)]TJ
0.0125 Tw T*
[(disease, with elevated levels of IL-4, IL-6, and IL-10. )17.7 (TNF-)]TJ
/T1_1 1 Tf
0 Tc 0 Tw T*
(\002)Tj
/T1_0 1 Tf
-0.00011 Tc 0.08 Tw 0.9609 0 Td
(levels have been shown to be low in SLE, and the pres-)Tj
0.09039 Tw -0.9609 -1.2 Td
[(ence of )17.7 (TNF-)]TJ
/T1_1 1 Tf
0 Tc 0 Tw [0.1 (\002)]TJ
/T1_0 1 Tf
-0.00011 Tc 0.09039 Tw 6.52 0 Td
(has been suggested to provide a protective)Tj
-0.03439 Tw -6.5199 -1.2 Td
(function. In the New Zealand black )Tj
/T1_1 1 Tf
0 Tc 0 Tw 14.2036 0 Td
(\004)Tj
/T1_0 1 Tf
-0.00011 Tc -0.03439 Tw 0.7644 0 Td
(New Zealand white F1)Tj
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(mouse model of SLE, blockade of IL-10 by anti-IL-10 anti-)Tj
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(body delayed the onset of clinical SLE)Tj
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(9)Tj
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[(. This )-17.7 (protective)]TJ
-0.03059 Tw -17.0743 -1.2 Td
[(ef)17.7 (fect was thought to be due to upregulation of )17.7 (TNF-)]TJ
/T1_1 1 Tf
0 Tc 0 Tw 20.8759 0 Td
(\002)Tj
/T1_0 1 Tf
-0.00011 Tc -0.03059 Tw 0.8503 0 Td
(as the)Tj
0.1756 Tw -21.7262 -1.2 Td
[(ef)17.7 (fect was blocked by the use of anti-TNF-)]TJ
/T1_1 1 Tf
0 Tc 0 Tw 18.3977 0 Td
(\002)Tj
/T1_0 1 Tf
-0.00011 Tc 0.1579 Tw [0.1 (. While )-17.7 (this)]TJ
0.3206 Tw -18.3977 -1.2 Td
(switch may explain the development of autoantibodies,)Tj
0.12959 Tw T*
(which is a common phenomenon, the presence of clinical)Tj
0.2014 Tw T*
(SLE is not, and there may be an additional, presumably)Tj
0.0164 Tw T*
[(genetic, factor)54.8 (. One prototype of this would be the develop-)]TJ
0.1597 Tw T*
(ment of a lupus-like syndrome with penicillamine, which)Tj
0.1275 Tw T*
(appears to be most frequent in individuals who are HLA-)Tj
0.02499 Tw T*
(DR3 positive)Tj
0 Tc 0 Tw 6.5 0 0 6.5 107.3018 416.4616 Tm
(10)Tj
10 0 0 10 113.8017 413.1616 Tm
(.)Tj
-0.00011 Tc 0.3736 Tw -4.7802 -1.22 Td
[(Evidence is also mounting that vasculitis is a )17.7 (Th2)]TJ
0.0042 Tc 0.3707 Tw -1.2 -1.22 Td
[(lymphocyte-mediated disease. One study in )17.8 (W)79.9 (egener)-37 (\325)55.1 (s)]TJ
-0.00011 Tc 0 Tw 0 -1.22 TD
(granulomatosis)Tj
-0.0567 Tc 6.5 0 0 6.5 115.0962 379.8617 Tm
(11)Tj
-0.00011 Tc 0.2234 Tw 10 0 0 10 125.9616 376.5616 Tm
(found increased expression of IL-4 and)Tj
0.0103 Tw -7.1962 -1.22 Td
(down-regulation of IL-2 in the nasal mucosa of newly diag-)Tj
0.0222 Tw T*
(nosed patients. In the Brown Norway rat, mercuric chloride)Tj
0.1003 Tw T*
(induces a necrotizing leukocytoclastic vasculitis in the gut)Tj
0.29379 Tw T*
[(with milder manifestations in the lung, liver)39.7 (, skin, and)]TJ
0 Tw T*
(kidney)Tj
0 Tc 6.5 0 0 6.5 81.2168 318.8617 Tm
(12)Tj
-0.00011 Tc -0.0298 Tw 10 0 0 10 87.7167 315.5616 Tm
[(. )17.8 (There is evidence that this is a )17.8 (Th2 response in that)]TJ
0.06799 Tw -3.3717 -1.22 Td
[(there is a )17.7 (T)-300.1 (cell-dependent polyclonal rise in immunoglob-)]TJ
0.0833 Tw T*
[(ulin. )17.7 (This rise can be blocked by the use of anti-IL-4 anti-)]TJ
0.02 Tc 0 Tw T*
(body)Tj
6.5 0 0 6.5 74.7999 282.2617 Tm
(13)Tj
0.4792 Tw 10 0 0 10 81.5597 278.9616 Tm
(. Support for this assertion comes from the)Tj
-0.00011 Tc 0.2812 Tw -2.756 -1.22 Td
(observation that there is upregulation of IL-4 mRNA)Tj
0 Tc 0 Tw 6.5 0 0 6.5 285.0002 270.0617 Tm
(14)Tj
10 0 0 10 291.5002 266.7617 Tm
(.)Tj
-0.00011 Tc 0.17191 Tw -23.75 -1.22 Td
(When D-penicillamine and gold salts are administered to)Tj
0.09641 Tw T*
(these rats, a similar leukocytoclastic vasculitis develops in)Tj
0.02499 Tw T*
(association with the upregulation of IL-4 mRNA)Tj
0 Tc 0 Tw 6.5 0 0 6.5 250.4391 233.4617 Tm
(15)Tj
10 0 0 10 256.939 230.1617 Tm
(.)Tj
0.0199 Tc 0.5493 Tw -19.0939 -1.2 Td
(Patients with preexisting autoantibodies may be)Tj
-0.00011 Tc 0.0174 Tw -1.2 -1.2 Td
[(reflecting the predominance of a )17.7 (Th2 response; the addition)]TJ
0.1086 Tw 0 -1.2 TD
(of anti-TNF therapy may promote increased expression of)Tj
0.02499 Tw T*
(this phenotype with consequent vasculitis.)Tj
-0.00301 Tw 1.2 -1.2 Td
(These mechanisms are at present speculative, and further)Tj
0.02499 Tw -1.2 -1.2 Td
[(investigation is required to define actual causality)64.8 (.)]TJ
0.27769 Tw 1.2 -1.2 Td
[(W)79.9 (orldwide experience with anti-TNF therapy is now)]TJ
0.04289 Tw -1.2 -1.2 Td
(extensive; most reactions are minor and related to injection)Tj
0.254 Tw T*
(or infusion. In our experience of over 700 infusions of)Tj
0.1394 Tw T*
[(infliximab involving 78 patients with RA)-334.6 (there have only)]TJ
-0.0224 Tw T*
(been 7 other adverse events necessitating dose modification.)Tj
0.0952 Tw T*
(Five of these reactions were rashes, one patient developed)Tj
-0.0235 Tw T*
(significant mouth ulceration, and the final patient had a flare)Tj
-0.0251 Tc 0.0748 Tw 26.4 63.9 Td
[(of joint disease. )54.9 (All of these reactions occurred early)64.9 (, typically)]TJ
-0.0097 Tc 0.3596 Tw T*
(by the fourth infusion. Subsequent infusions have been)Tj
-0.0251 Tc 0.013 Tw T*
[(uneventful. )17.8 (W)79.9 (e would suggest that while infliximab and etaner-)]TJ
0.0112 Tw T*
(cept therapy is generally safe, the occurrence of rare but serious)Tj
0.0226 Tw T*
(events shows the need for watchfulness and the involvement of)Tj
0.09309 Tw T*
(physicians experienced in the use of such agents, especially if)Tj
0.02499 Tw T*
(being considered for the treatment of vasculitis. )Tj
/T1_2 1 Tf
-0.00011 Tc 0 Tw 0 -2.4 TD
(REFERENCES)Tj
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[(1.)-875.1 (Shakoor N, Michalska M, Harris CA, Block JA. Drug-induced)]TJ
1.675 -1.25 Td
[(systemic lupus erythematosus associated with etanercept therapy)64.8 (.)]TJ
0 -1.25 TD
(Lancet 2002;359:579-80.)Tj
-1.675 -1.25 Td
[(2.)-875.1 (Charles PJ, Smeek RJ, De Jong J, Feldman M, Maini RN.)]TJ
1.675 -1.25 Td
[(Assessment of antibodies to double-stranded DNA)-220.2 (induced in)]TJ
T*
(rheumatoid arthritis patients following treatment with infliximab, a)Tj
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(monoclonal antibody to tumor necrosis factor alpha: findings in)Tj
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[(open-label and randomised placebo-controlled trials. )54.8 (Arthritis)]TJ
0 Tc T*
(Rheum 2000;43:2381-2.)Tj
-0.00011 Tc -1.675 -1.25 Td
[(3.)-875.1 (Robinson )17.7 (WH, Genovese MC, Moreland L)73.9 (W)91.9 (. Demyelinating and)]TJ
1.675 -1.25 Td
(neurologic events reported in association with tumor necrosis factor)Tj
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(alpha antagonism. By what mechanism could tumor necrosis factor)Tj
T*
(alpha antagonists improve rheumatoid arthritis but exacerbate)Tj
T*
[(multiple sclerosis? )54.8 (Arthritis Rheum 2001;44:1977-83.)]TJ
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[(4.)-875.1 (Galaria N, )17.7 (W)79.9 (erth )17.7 (VP)110.8 (, Schumacher HR. Leukocytoclastic vasculitis)]TJ
1.675 -1.25 Td
(due to etanercept. J Rheumatol 2000;27:2041-4.)Tj
-1.675 -1.25 Td
[(5.)-875.1 (den Broeder )54.8 (AA, van den Hoogen FHJ, van de Putte LBA. Isolated)]TJ
1.675 -1.25 Td
(digital vasculitis in a patient with rheumatoid arthritis: good)Tj
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[(response to tumour necrosis factor alpha blocking treatment. )54.8 (Ann)]TJ
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(Rheum Dis 2001;60:538-9.)Tj
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[(6.)-875.1 (Maini RN, Breedveld FC, Kalden JR, et al. )17.7 (Therapeutic ef)17.7 (ficacy of)]TJ
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(multiple intravenous infusions of anti-tumour necrosis factor alpha)Tj
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(monoclonal antibody combined with weekly low dose methotrexate)Tj
T*
[(in rheumatoid arthritis. )54.8 (Arthritis Rheum 1996;41:1552-64.)]TJ
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[(7.)-875.1 (Smolen JS, Steiner G, Breedveld FC, et al. )54.8 (Anti-TNF alpha therapy)]TJ
1.675 -1.25 Td
[(and drug induced-lupus-like syndrome [abstract]. )54.8 (Ann Rheum Dis)]TJ
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(1999;217 Suppl:906.)Tj
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[(8.)-875.1 (W)79.9 (einblatt ME, Kremer JM, Bankhurst )54.8 (AD, Bulpitt KJ, Fleishmann)]TJ
1.675 -1.25 Td
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(factor receptor:Fc fusion protein, in patients with rheumatoid)Tj
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(arthritis receiving methotrexate. N Engl J Med 1999;340:253-9.)Tj
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(Howard M. Continuous administration of anti-interleukin 10 )Tj
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[(antibodies delays the onset of autoimmunity in NZB/W)-257.3 (F1 mice. )]TJ
0 Tc T*
(J Exp Med 1994;179:305-10.)Tj
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[(10.)-875.1 (Emery P)110.7 (, Panayi GS, Huston G, et al. D-penicillamine induced )]TJ
2.175 -1.25 Td
(toxicity in rheumatoid arthritis: the role of sulphoxidation status)Tj
T*
[(and HLA-DR3. J Rheumatol 1984;1)36.8 (1:626-32.)]TJ
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[(1)36.8 (1)-0.1 (.)-875.1 (Balding CEJ, Howie )54.8 (AJ, Drake-Lee )54.8 (AB, Savage COS. )17.7 (Th2 )]TJ
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[(dominance in nasal mucosa in patients with )17.7 (W)79.9 (egener)-37 (\325)55.1 (s )]TJ
T*
(granulomatosis. Clin Exp Immunol 2001;125:332-9.)Tj
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[(12.)-875.1 (Mathieson PW)91.7 (, )17.7 (Thiru S, Oliveira DBG. Mercuric chloride-treated)]TJ
2.175 -1.25 Td
(Brown Norway rats develop widespread tissue injury including)Tj
T*
(necrotising vasculitis. Lab Invest 1992;67:121-9.)Tj
-2.175 -1.25 Td
[(13.)-875.1 (Ochel M, )17.7 (V)128.9 (ohr HW)91.7 (, Pfeif)17.7 (fer C, et al, IL-4 is required for the IgE)]TJ
2.175 -1.25 Td
(and IgG1 increase and IgG1 autoantibody formation in mice treated)Tj
T*
[(with mercuric chloride. J Immunol 1991;146:306-1)36.8 (1.)]TJ
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[(14.)-875.1 (Gillespie KM, Qasim FJ, )17.7 (T)35 (ibbatts LM, et al. Interleukin-4 gene)]TJ
2.175 -1.25 Td
[(expression in mercury-induced autoimmunity)64.8 (. Scand J Immunol)]TJ
0 Tc 0 Tw T*
(1995;41:268-72.)Tj
-0.00011 Tc 0.02499 Tw -2.175 -1.25 Td
[(15.)-875.1 (Quasim FJ, )17.7 (Thiru S, Gillespie K. Gold and D-penicillamine induce)]TJ
2.175 -1.25 Td
[(vasculitis and up-regulate mRNA)-220.2 (for IL-4 in the Brown Norway)]TJ
T*
[(Rat: support for a role for )17.7 (Th2 cell activity)64.9 (. Clin Exp Immunol)]TJ
0 Tc 0 Tw T*
(1997;108:438-45.)Tj
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/T1_3 1 Tf
-0.00011 Tc 0.02499 Tw 8 0 0 8 54.5 36.0898 Tm
[(Jarr)36.8 (ett, et al: )17.7 (Anti-TNF-)]TJ
/T1_1 1 Tf
0 Tc 0 Tw 8 0 1.7005 8 132.4164 36.0898 Tm
(\002)Tj
/T1_3 1 Tf
-0.00011 Tc 0.02499 Tw 8 0 0 8 139.6633 36.0898 Tm
(therapy and vasculitis)Tj
0 Tc 0 Tw 50.2921 -0.0444 Td
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(Personal, non-commercial use only. The Journal of Rheumatology Copyrig\
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