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This article is part of the supplement: Current perspectives on the treatment of rheumatic diseases with infliximab

Supplement

Emerging role of anti-tumor necrosis factor therapy in rheumatic diseases

Joachim R Kalden

Author Affiliations

Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nurnberg, Erlangen, Germany

Arthritis Res 2002, 4(Suppl 2):S34-S40  doi:10.1186/ar552

The electronic version of this article is the complete one and can be found online at: http://arthritis-research.com/content/4/S2/S34


Received:3 December 2001
Revisions received:24 January 2002
Accepted:28 March 2002
Published:24 May 2002

© 2002 BioMed Central Ltd

Abstract

Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine that has been implicated in a variety of rheumatic and inflammatory diseases. New understanding of the importance of TNF-α in the pathophysiology of rheumatoid arthritis and Crohn's disease led to the development of a new class of targeted anti-TNF therapies. Anti-TNF-α agents including etanercept (a fusion protein of the p75 TNF receptor and IgG1) and infliximab (a chimeric monoclonal antibody specific for TNF-α) have been approved for the treatment of rheumatoid arthritis. In addition, infliximab has been approved in the treatment of patients with active or fistulating Crohn's disease. A new appreciation of the importance of TNF-α in other rheumatic and inflammatory diseases has led to a broadening of the application of anti-TNF agents. Both etanercept and infliximab have been used in open-label and randomized studies in patients with psoriatic arthritis. Although larger randomized trials are needed to confirm early results, both these anti-TNF-α agents, etanercept and infliximab, have demonstrated activity in improving the signs and symptoms of psoriatic arthritis and psoriasis. Infliximab has also been shown to be effective in patients with other rheumatic diseases, including ankylosing spondylitis, and may be effective in adult-onset Still's disease, polymyositis, and Behçet's disease. Further investigations will fully elucidate the role of infliximab in these and other rheumatic diseases.

Keywords:
anti-tumor necrosis factor; cytokine; infliximab; rheumatic disease; tumor necrosis factor

Introduction

Significant advances in recent years have improved the understanding of the pathogenesis of rheumatoid arthritis (RA). It is thought that TNF-α resides at the apex of an inflammatory cytokine cascade that is responsible for the pathophysiology of RA. The central role for TNF-α in RA is supported by several findings. Secreted by cultured synoviocytes, TNF-α is elevated in sera and synovial fluid of RA patients [1-3]. In addition, anti-TNF-α antibodies have been shown to prevent polyarthritic disease in two mouse models [4,5].

The new appreciation of the importance of TNF-α in the pathophysiology of RA has led to the clinical development of a new class of targeted therapeutic agents. Etanercept (Enbrel®; Immunex, Seattle, WA, USA) is a fusion protein of the extracellular ligand-binding portion of the p75 TNF receptor and the Fc portion of IgG1. Etanercept binds to soluble TNF-α and lymphotoxin-α, thus blocking the activation of TNF receptors. Infliximab (Remicade®; Centocor, Malvern, PA, USA) is a chimeric (human/mouse) antibody that binds with high affinity and specificity to both the soluble and membrane-bound forms of TNF-α. In addition, infliximab also binds to TNF-α already engaged with the TNF receptor. Infliximab thus neutralizes soluble and membrane-bound TNF-α and can inhibit the activation of TNF receptors before and after TNF-α engages with the receptor.

Both etanercept and infliximab have demonstrated efficacy in reducing the signs and inflammatory symptoms of RA and in inhibiting joint erosion in clinical trials [6-10]. In addition, infliximab has been shown to significantly inhibit joint space narrowing [10].

Etanercept and infliximab have both been approved for the treatment of RA by the US Food and Drug Administration and by the European Agency for the Evaluation of Medicinal Products. In addition, infliximab has been approved for the treatment of Crohn's disease in patients with moderately to severely active or fistulating disease [11,12]. Success in the treatment of these inflammatory diseases with anti-TNF agents has prompted the investigation of this therapeutic modality in the treatment of other rheumatic diseases, including psoriatic arthritis (PsA), ankylosing spondylitis (AS), adult-onset Still's disease (AOSD), and polymyositis.

Current diseases under investigation

The use of anti-TNF agents in the treatment of PsA, AS, AOSD, and polymyositis has been based on evidence suggesting that TNF plays a role in these inflammatory rheumatic diseases. In the present article, the evidence of activity of anti-TNF-α therapy in the treatment of these diseases will be reviewed.

PsA and psoriasis

Psoriasis is reported to affect between 1 and 3% of adults in the United States, and PsA occurs in approximately 6–20% of psoriasis patients [13]. PsA is an inflammatory arthropathy that may present in a symmetric or an asymmetric polyarticular form, with or without onycholysis. The current therapeutic approaches for PsA are similar to those for RA and include nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs (DMARDs), and immunosuppressive agents. Only two DMARDs, methotrexate (MTX) [14] and sulfasalazine [15], have demonstrated efficacy in the treatment of PsA. These agents are, however, associated with significant adverse events, and many patients do not respond to these treatments. Other therapeutic options are therefore needed.

TNF-α has been linked to the pathogenesis of PsA and psoriasis because of its ability to upregulate adhesion molecules and to trigger an inflammatory cytokine cascade. TNF-α induces the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, both of which are involved in lymphocyte trafficking to inflammatory lesions [16]. Circulating T lymphocytes and macrophages isolated from PsA patients produce an increased amount of TNF-α compared with macrophages isolated from healthy controls [17]. Furthermore, the levels of TNF-α are elevated in the synovial fluid [18,19] and skin lesions [20,21] in PsA patients, with TNF-α levels correlated with disease activity [22,23].

Several open-label studies have investigated the use of anti-TNF-α agents in the treatment of PsA and psoriasis [24-28]. In a single-center, open-label report on the treatment of spondyloarthopathies, Van den Bosch et al. [24] reported that nine PsA patients treated with 5 mg/kg infliximab (weeks 0, 2, and 6) experienced significant improvement in physician's global assessment (PGA) scores, erythrocyte sedimentation rates (ESRs), and C-reactive protein (CRP) levels. Of these nine patients, eight had psoriasis at baseline. After 12 weeks of infliximab treatment, baseline Psoriasis Area and Severity Index (PASI) scores were significantly decreased (improved). The clinical improvements in all PsA and psoriasis disease manifestations were maintained over a 1-year follow-up period [25].

In another open-label study, eight out of 10 heavily pre-treated PsA patients experienced improvements in Health Assessment Questionnaire scores and PGA scores after 12 months of treatment with 25 mg etanercept (subcutaneously, twice per week). All four patients in this trial with active psoriasis had significant improvement in their psoriatic lesions, including complete resolution in three patients [26].

In our open-label experience, infliximab treatment was efficacious and safe in both PsA and psoriasis [27,28]. With infliximab treatment (5 mg/kg at weeks 0, 2, and 6), all 10 patients in our study achieved 20% improvement in arthritis per the American College of Rheumatology response criteria (ACR) by week 2. After 10 weeks of treatment, eight patients achieved 70% improvement per the ACR, with six patients maintaining this improvement after 54 weeks. In addition, magnetic resonance imaging showed an 82% reduction in inflammation in peripheral joints, and mean PASI scores were reduced by 71% at week 10. After 10 weeks of infliximab therapy, six patients experienced nearly complete clearing of erythematous psoriasis plaques (Fig. 1). Furthermore, histopathologic analysis of psoriatic plaques showed a reduction in epidermal hyperplasia and inflammation by week 10 (Fig. 2). This reduction in hyperplasia was associated with a decrease in plaque size and was evident from the near-normal epidermal structure after infliximab treatment.

thumbnailFigure 1. Psoriasis plaques on patient skin. Depicted is a representative set of patient plaques (a) before and (b) 10 weeks after infliximab treatment. Note the characteristic sharply circumscribed erythematous psoriasis plaque covered by silvery scales prior to infliximab therapy.

thumbnailFigure 2. Histopathologic psoriasis plaques. Epidermal and dermal characteristics of psoriasis plaques from a representative patient (a) before and (b) 10 weeks after infliximab treatment.

The use of anti-TNF agents in treating PsA and psoriasis has also been investigated in randomized, double-blinded, placebo-controlled studies. Mease et al. [29] reported that 87% of patients receiving 25 mg etanercept (subcutaneously, twice per week) achieved Ps ACR response criteria, compared with 23% of placebo patients (P < 0.0001). Seventy-three per cent of etanercept-treated patients achieved 20% improvement of the ACR, compared with 13% of placebo-treated patients (P < 0.0001). Of 19 patients in each treatment group with active psoriasis, the median improvement in PASI scores was significantly higher in etanercept-treated patients than that in placebo-treated patients. Of the psoriasis patients treated with etanercept, 26% achieved a 75% improvement, compared with no patients treated with placebo. In an open-label extension study, etanercept continued to effectively reduce clinical signs and symptoms of PsA and psoriasis for up to 36 weeks [30].

Chaudhari et al. [31] recently described the first reported placebo-controlled, randomized study designed to investigate the efficacy of an anti-TNF agent in psoriasis patients. In this study, 30 patients were randomized to receive 5 mg/kg or 10 mg/kg infliximab or placebo. Nine of 11 (82%) patients treated with 5 mg/kg infliximab achieved good, excellent, or clear ratings on PGA, compared with only two of 11 (18%) patients receiving placebo (P = 0.0089). In addition, 10 of 11 (91%) patients treated with 10 mg/kg infliximab achieved these ratings (P = 0.0019, compared with placebo). A significantly higher proportion (P = 0.0089, 5 mg/kg infliximab versus placebo; P = 0.03, 10 mg/kg infliximab versus placebo) of patients treated with infliximab obtained a 75% improvement in PASI scores compared with those receiving placebo. The results of these studies suggest that TNF-α plays a pivotal role in the pathogenesis of PsA and psoriasis. In addition, anti-TNF-α therapy offers patients with PsA and psoriasis a new therapeutic option for the control of their disease.

Ankylosing spondylitis

AS is an inflammatory arthropathy that preferentially affects the axial skeleton, usually manifesting in the sacroiliac joints and then ascending to involve the axial skeleton [32,33]. Treatment for AS includes nonsteroidal anti-inflammatory drugs and sulfasalazine, the only DMARD that shows activity, albeit limited, in the disease [34].

Only limited evidence exists to support a role for TNF-α in the pathophysiology of AS. Braun et al. [35] showed that TNF-α mRNA and protein were present in inflamed sacroiliac joints of AS patients. Lange et al. [36] recently reported significantly increased TNF-α plasma levels in AS patients, with a positive correlation between TNF-α plasma levels and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). In addition, the strong link between AS and inflammatory bowel disease (where 20–60% of spondyloarthropathy patients have gastrointestinal lesions resembling those in Crohn's disease) provides circumstantial evidence for a role of TNF-α in AS [37].

Despite a general lack of evidence for a role of TNF-α in the pathophysiology of AS, clinicians are beginning to investigate the use of anti-TNF therapies in this inflammatory disease. In an open-label study, 11 patients with AS of short duration were treated with 5 mg/kg infliximab at weeks 0, 2, and 6 [38]. Improvements in activity, in function, and in pain scores of ≥ 50% were reported in nine of 10 eligible patients. The median CRP level decreased to normal levels and the median improvement in BASDAI scores after 4 weeks was 70%.

In another open-label study of patients with different sub-types of spondyloarthropathy, 10 AS patients treated with 5 mg/kg infliximab every 14 weeks achieved significant improvements in morning stiffness, tender and swollen joint counts, ESR, CRP, and BASDAI, Bath Ankylosing Spondylitis Functional Index, and Bath Ankylosing Spondylitis Metrology Index scores. Improvement in ESR and CRP was significant at day 3 after infliximab treatment and was maintained to day 84. Improvements in the other endpoints were significant at day 14 and were also maintained to day 84. The significant improvements in the global, peripheral, and axial disease manifestations were maintained over a 1-year follow-up period [25].

In a larger open-label study, 48 patients with severe AS were treated with infliximab. Significant improvements in mean disease activity, global pain, BASDAI, Bath Ankylosing Spondylitis Functional Index scores, and CRP levels were observed at week 8 [39].

The results of the aforementioned open-label studies were recently confirmed in a double-blind, placebo-controlled, phase III clinical trial [40]. A total of 70 patients with active AS were enrolled in the study and were randomized to receive placebo (n = 35) or to receive 5 mg/kg infliximab (n = 35) at weeks 0, 2, and 6, and then every 6 weeks until week 48. At the time of the report, 66 patients had completed 3 months of treatment. A 50% improvement in BASDAI was achieved by 53% of patients treated with infliximab, compared with 9% of patients treated with placebo (P < 0.01).

Adult-onset Still's disease

AOSD is a rare systemic inflammatory disorder of unknown etiology. Clinical symptoms of this disease are high spiking fever, arthritis, transient cutaneous rashes, and sore throat [41]. AOSD is considered identical to the systemic form of juvenile RA [42]. A markedly elevated serum ferritin correlates with disease activity [43,44], and several inflammatory cytokines (e.g. IL-18) are elevated in these patients [45-47]. Furthermore, Hoshino et al. [46] reported elevated serum levels of TNF-α in AOSD patients. Kawashima et al. [47] recently demonstrated that the proinflammatory cytokine IL-18 is markedly elevated in the serum of AOSD patients during the acute phase of their disease. Because it has been shown that TNF-α induces the expression of IL-18 in synovial tissues [48], anti-TNF agents may lead to a reduction of IL-18 in AOSD patients. Bombardieri et al. [49] recently demonstrated that infliximab reduced IL-18 serum levels in RA patients. Studies to determine whether infliximab also reduces IL-18 serum levels in AOSD are therefore warranted.

The current treatment for AOSD is mostly limited to the use of nonsteroidal anti-inflammatory drugs and, in severe cases, of prednisone. However, many patients become dependent on high-dose prednisone or are refractory to corticosteroid treatment. In a retrospective analysis of 26 AOSD patients, MTX was an effective second-line treatment for patients who had not responded to prednisone [50]. However, controlled studies of MTX and other DMARDs in the treatment of AOSD have not been performed.

Interest in using anti-TNF therapy in treating AOSD increased following a report that infliximab was effective in suppressing fever and acute phase response in a patient with juvenile chronic arthritis [51]. Furthermore, thalidomide, a known inhibitor of TNF-α, was reported to markedly improve clinical symptoms in a patient with treatment-resistant AOSD [52]. Systematic investigation of anti-TNF-α therapy in AOSD is in its early stages. An open-label trial evaluated the efficacy of infliximab in the treatment of AOSD refractory to conventional therapy [53]. Three patients with chronic and active AOSD who were unresponsive to corticosteroids and MTX were administered 3 mg/kg infliximab at weeks 0, 2, and 6, and then every 8 weeks thereafter, along with concomitant 15 mg/week MTX. Disease activity had improved in all three patients at 50 weeks of follow-up, and two patients experienced reductions in ESR, CRP, prednisone dose, and PGA score.

In a recent pilot study conducted at our institution, six AOSD patients treated with infliximab reported marked improvements in the clinical signs and symptoms of AOSD [54]. Patients were treated with 5 mg/kg infliximab at weeks 0, 2, and 6, and thereafter at intervals of 6–8 weeks. Fever, arthralgias, myalgias, splenomegaly, and rash were resolved in all six patients within the first three courses of infliximab treatment. A summary of the serologic and disease activity parameters is presented in Table 1. Although the results of these open-label trials need to be confirmed in randomized, placebo-controlled studies, the preliminary results suggest infliximab is effective in managing relapse in refractory AOSD patients.

Table 1. Serologic and global assessment parameters in patients with adult-onset Still's disease receiving 5 mg/kg infliximab

Polymyositis

Polymyositis is an idiopathic inflammatory myopathy that is characterized by proximal muscle weakness, skeletal muscle inflammation and damage, and elevated serum levels of muscle-derived proteins such as creatinine kinase. Polymyositis is associated with lymphocyte invasion of muscle fibers, predominantly cytotoxic CD8+ T lymphocytes, which leads to muscle fiber necrosis, degeneration, and fibrosis. The current first-line therapy for polymyositis is prednisone [55]. However, many patients only achieve partial response or do not respond at all to high-dose corticosteroids. Because early recognition and treatment of polymyositis is critical to prevent irreversible muscle damage, second-line therapies such as MTX or azathioprine should be administered to patients who fail corticosteroid treatment [55].

Tateyama et al. [56] demonstrated, using monoclonal antibodies to TNF-α, that TNF-α-positive macrophages and lymphocytes invade the endomysium in the muscles of polymyositis patients. In addition, there was a correlation between TNF-α levels in the endomysium and muscle fiber atrophy. Kuru et al. [57] also demonstrated infiltration of TNF-α-positive CD8+ lymphocytes and macrophages into the muscle fibers of polymyositis patients.

The apparent involvement of cytokine-producing T lymphocytes in polymyositis initiated interest in treating these patients with anti-TNF agents. There have been no published accounts of the efficacy of anti-TNF therapy in polymyositis, but a number of case studies have been presented. We recently treated a patient with polymyositis refractory to immunosuppressive regimens with 4 mg/kg infliximab every 6 weeks and concomitant MTX therapy. This patient showed a significant response on infliximab treatment, including a significant improvement in mobility. The skeletal muscle-specific enzymes returned to normal serum levels, indicating a substantial reduction in inflammation. Although this is a single case study, it suggests that anti-TNF-α therapy may be a viable treatment alternative for patients with refractory polymyositis. Further studies to fully investigate the potential for anti-TNF-α therapy in treating polymyositis are warranted.

Behçet's disease

Behçet's disease is a chronic autoimmune disorder characterized by systemic vasculitis. This disease is associated with mucocutaneous, ocular, articular, vascular, gastrointestinal, and central nervous system manifestations. Approximately 70% of patients experience relapsing ocular inflammation that can lead to blindness [58]. The etiology of Behçet's disease is unknown; however, some evidence suggests that increased levels of TNF and soluble TNF receptors are associated with active disease [59-61]. Interestingly, thalidomide, which has been used successfully in the treatment of Behcet's disease, inhibits TNF-α by accelerating the degradation of TNF-α mRNA [62]. Other anti-TNF therapies may therefore benefit these patients.

Anti-TNF therapy has recently been used for the treatment of patients with Behçet's disease. Travis et al. [63] reported the successful use of infliximab in two patients with Behçet's disease with rare gastrointestinal ulcerations. Within 10 days of infliximab treatment, the ulcers had healed and all extraintestinal manifestations had resolved. Furthermore, five patients with relapsing panuveitis were successfully treated with infliximab. Remission of ocular inflammation was evident within the first 24 hours, and complete suppression was observed within 7 days of infliximab therapy [64]. The rapid and effective response of this handful of patients with Behçet's disease to infliximab clearly warrants further studies of the use of anti-TNF therapy in treating this disease.

Conclusions

Anti-TNF-α therapy is currently approved for the treatment of RA (infliximab in combination with MTX, and etanercept) and of Crohn's disease (infliximab). This brief summary of study data supports a role for anti-TNF therapy in the treatment of PsA, psoriasis, AS, AOSD, polymyositis, and Behçet's disease. Success in the treatment of these inflammatory disorders suggests that anti-TNF therapy may also be effective in treating other inflammatory diseases, including ulcerative colitis, uveitis, and Felty's syndrome. Future investigations will determine the breadth of application of anti-TNF therapy in the treatment of autoimmune and inflammatory disorders.

Note added in proof

In January 2002, etanercept was awarded an additional indication by the US Food and Drug Administration. Etanercept was approved as monotherapy or in combination with methotrexate for reducing the signs and symptoms of psoriatic arthritis.

Abbreviations

ACR = American College of Rheumatology response criteria; AOSD = adult-onset Still's disease; AS = ankylosing spondylitis; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; CRP = C-reactive protein; DMARD = disease-modifying antirheumatic drug; ESR = erythrocyte sedimentation rate; Fc = crystallizable fragment; IL = interleukin; MTX = methotrexate; PASI = Psoriasis Area and Severity Index; PGA = physician's global assessment; PsA = psoriatic arthritis; RA = rheumatoid arthritis; TNF-α = tumor necrosis factor alpha.

References

  1. Brennan FM, Chantry D, Jackson AM, Maini RN, Feldmann M: Cytokine production in culture by cells isolated from the synovial membrane.

    J Autoimmun 1989, 22:177-186. Publisher Full Text OpenURL

  2. Chu CQ, Field M, Feldmann M, Maini RN: Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis.

    Arthritis Rheum 1991, 34:1125-1132. PubMed Abstract OpenURL

  3. Feldmann M, Brennan FM, Maini RN: Role of cytokines in rheumatoid arthritis.

    Annu Rev Immunol 1996, 14:397-440. PubMed Abstract | Publisher Full Text OpenURL

  4. Williams RO, Feldmann M, Maini RN: Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis.

    Proc Natl Acad Sci USA 1992, 89:9784-9788. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  5. Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, Kollias G: Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis.

    EMBO J 1991, 10:4025-4031. PubMed Abstract OpenURL

  6. Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H, Woody JN: Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis.

    Lancet 1994, 344:1105-1110. PubMed Abstract | Publisher Full Text OpenURL

  7. Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL, Ettlinger RE, Cohen S, Koopman WJ, Mohler K, Widmer MB, Blosch CM: Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein.

    N Engl J Med 1997, 337:141-147. PubMed Abstract | Publisher Full Text OpenURL

  8. Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, Genovese MC, Wasko MC, Moreland LW, Weaver AL, Markenson J, Finck BK: A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.

    N Engl J Med 2000, 343:1586-1593. PubMed Abstract | Publisher Full Text OpenURL

  9. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, Antoni C, Leeb B, Elliott MJ, Woody JN, Schaible TF, Feldmann M: Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis.

    Arthritis Rheum 1998, 41:1552-1563. PubMed Abstract | Publisher Full Text OpenURL

  10. Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, Harriman GR, Maini RN: Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis With Concomitant Therapy Study Group.

    N Engl J Med 2000, 343:1594-1602. PubMed Abstract | Publisher Full Text OpenURL

  11. Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, DeWoody KL, Schaible TF, Rutgeerts PJ: A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group.

    N Engl J Med 1997, 337:1029-1035. PubMed Abstract | Publisher Full Text OpenURL

  12. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL, Schaible TF, van Deventer SJ: Infliximab for the treatment of fistulas in patients with Crohn's disease.

    N Engl J Med 1999, 340:1398-1405. PubMed Abstract | Publisher Full Text OpenURL

  13. Smiley JD: Psoriatic arthritis.

    Bull Rheum Dis 1995, 44:1-2. PubMed Abstract OpenURL

  14. Willkens RF, Williams HJ, Ward JR, Egger MJ, Reading JC, Clements PJ, Cathcart ES, Samuelson CO Jr, Solsky MA, Kaplan SB, Guttadauria M, Halla JT, Weinstein A: Randomized, double-blind, placebo controlled trial of low-dose pulse methotrexate in psoriatic arthritis.

    Arthritis Rheum 1984, 27:376-381. PubMed Abstract OpenURL

  15. Clegg DO, Reda DJ, Mejias E, Cannon GW, Weisman MH, Taylor T, Budiman-Mak E, Blackburn WD, Vasey FB, Mahowald ML, Cush JJ, Schumacher HR Jr, Silverman SL, Alepa FP, Luggen ME, Cohen MR, Makkena R, Haakenson CM, Ward RH, Manaster BJ, Anderson RJ, Ward JR, Henderson WG: Comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis. A Department of Veterans Affairs Cooperative Study.

    Arthritis Rheum 1996, 39:2013-2020. PubMed Abstract OpenURL

  16. Wakefield PE, James WD, Samlaska CP, Meltzer MS: Tumor necrosis factor.

    J Am Acad Dermatol 1991, 24:675-685. PubMed Abstract OpenURL

  17. Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG: The majority of epidermal T cells in psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients.

    J Invest Dermatol 1999, 113:752-759. PubMed Abstract | Publisher Full Text OpenURL

  18. Ritchlin C, Haas-Smith SA, Hicks D, Cappuccio J, Osterland CK, Looney RJ: Patterns of cytokine production in psoriatic synovium.

    J Rheumatol 1998, 25:1544-1552. PubMed Abstract OpenURL

  19. Danning CL, Illei GG, Hitchon C, Greer MR, Boumpas DT, McInnes IB: Macrophage-derived cytokine and nuclear factor kappaB p65 expression in synovial membrane and skin of patients with psoriatic arthritis.

    Arthritis Rheum 2000, 43:1244-1256. PubMed Abstract | Publisher Full Text OpenURL

  20. Ettehadi P, Greaves MW, Wallach D, Aderka D, Camp RD: Elevated tumour necrosis factor-alpha (TNF-alpha) biological activity in psoriatic skin lesions.

    Clin Exp Immunol 1994, 96:146-151. PubMed Abstract OpenURL

  21. Uyemura K, Yamamura M, Fivenson DF, Modlin RL, Nickoloff BJ: The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response.

    J Invest Dermatol 1993, 101:701-705. PubMed Abstract | Publisher Full Text OpenURL

  22. Bonifati C, Carducci M, Cordiali Fei P, Trento E, Sacerdoti G, Fazio M, Ameglio F: Correlated increases of tumour necrosis factor-alpha, interleukin-6 and granulocyte monocyte-colony stimulating factor levels in suction blister fluids and sera of psoriatic patients – relationships with disease severity.

    Clin Exp Dermatol 1994, 19:383-387. PubMed Abstract OpenURL

  23. Mussi A, Bonifati C, Carducci M, D'Agosto G, Pimpinelli F, D'Urso D, D'Auria L, Fazio M, Ameglio F: Serum TNF-alpha levels correlate with disease severity and are reduced by effective therapy in plaque-type psoriasis.

    J Biol Regul Homeost Agents 1997, 11:115-118. PubMed Abstract OpenURL

  24. Van den Bosch F, Kruithof E, Baeten D, De Keyser F, Mielants H, Veys EM: Effects of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor α (infliximab) in spondyloarthropathy: an open pilot study.

    Ann Rheum Dis 2000, 59:428-433. PubMed Abstract | Publisher Full Text OpenURL

  25. Kruithof E, Van den Bosch F, Baeten D, De Keyser F, Mielants H, Veys EM: TNF-alpha blockade with infliximab in patients with active spondyloarthropathy: follow-up of one year maintenance regimen [abstract].

    Ann Rheum Dis 2001, 60(suppl 1):59. OpenURL

  26. Yazici Y, Erkan D, Lockshin MD: A preliminary study of etanercept in the treatment of severe, resistant psoriatic arthritis.

    Clin Exp Rheumatol 2000, 18:732-734. PubMed Abstract OpenURL

  27. Antoni C, Dechant C, Lorenz H-M, Wendler J, Ogilvie A, Lüftl M, Kalden-Nemeth D, Kalden JR, Manger B: Successful treatment of psoriatic arthritis with infliximab in a MRI controlled study [abstract].

    Arthritis Rheum 1999, 42(suppl):s371. OpenURL

  28. Dechant C, Antoni C, Wendler J, Ogilvie ALJ, Lueftl M, Lorenz H-M, Kalden JR, Manger B: One year outcome of patients with severe psoriatic arthritis treated with infliximab [abstract].

    Arthritis Rheum 2000, 42(suppl):s102. OpenURL

  29. Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ: Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial.

    Lancet 2000, 356:385-390. PubMed Abstract | Publisher Full Text OpenURL

  30. Mease PJ, Goffe BS, Metz J, VanderStoep A, Burge DJ: Enbrel® (etanercept) in patients with psoriatic arthritis and psoriasis. Congress of Rheumatology [abstract].

    Ann Rheum Dis 2001, 60(suppl 1):146. PubMed Abstract | Publisher Full Text OpenURL

  31. Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB: Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial.

    Lancet 2001, 357:1842-1847. PubMed Abstract | Publisher Full Text OpenURL

  32. Braun J, Sieper J: The sacroiliac joint in the spondyloarthropathies.

    Curr Opin Rheumatol 1996, 8:275-287. PubMed Abstract OpenURL

  33. Braun J, Bollow M, Sieper J: Radiologic diagnosis and pathology of the spondyloarthropathies.

    Rheum Dis Clin North Am 1998, 24:697-735. PubMed Abstract OpenURL

  34. Toussirot E, Wendling D: Therapeutic advances in ankylosing spondylitis.

    Expert Opin Invest Drugs 2001, 10:21-29. Publisher Full Text OpenURL

  35. Braun J, Bollow M, Neure L, Seipelt E, Seyrekbasan F, Herbst H, Eggens U, Distler A, Sieper J: Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis.

    Arthritis Rheum 1995, 38:499-505. PubMed Abstract OpenURL

  36. Lange U, Teichmann J, Stracke H: Correlation between plasma TNF-alpha, IGF-1, biochemical markers of bone metabolism, markers of inflammation/disease activity, and clinical manifestations in ankylosing spondylitis.

    Eur J Med Res 2000, 5:507-511. PubMed Abstract OpenURL

  37. Mielants H, Veys EM, Cuvelier C, De Vos M: Course of gut inflammation in spondyloarthropathies and therapeutic consequences.

    Baillieres Clin Rheumatol 1996, 10:147-164. PubMed Abstract OpenURL

  38. Brandt J, Haibel H, Cornely D, Golder W, Gonzalez J, Reddig J, Thriene W, Sieper J, Braun J: Successful treatment of active ankylosing spondylitis with the anti-tumor necrosis factor α monoclonal antibody infliximab.

    Arthritis Rheum 2000, 43:1346-1352. PubMed Abstract | Publisher Full Text OpenURL

  39. Breban MA, Vignon E, Claudepierre P, Saraux A, Wendling D, Lespesailles E, Euller-Ziegler L, Sibilia J, Perdriger A, Alexandre C, Dougados M: Efficacy of infliximab in severe refractory ankylosing spondylitis (AS). Results of an open-label study [abstract].

    Ann Rheum Dis 2001, 60(suppl 1):59. OpenURL

  40. Brandt J, Alten R, Burmester G, Gromnica-Ihle E, Kellner H, Schneider M, Sörensen H, Zeidler H, Thriene W, Sieper J, Braun J: Three months results of a double-blind placebo controlled, phase-III clinical trial of infliximab in active ankylosing spondylitis [abstract].

    Ann Rheum Dis 2001, 60(suppl 1):61. PubMed Abstract | Publisher Full Text OpenURL

  41. Sanchez Loria DM, Moreno Alvarez MJ, Maldonado Cocco JA, Scheines EJ, Messina OD: Adult onset Still's disease: clinical features and course.

    Clin Rheumatol 1992, 11:516-520. PubMed Abstract OpenURL

  42. Bywaters EG: Still's disease in the adult.

    Ann Rheum Dis 1971, 30:121-133. PubMed Abstract OpenURL

  43. Ota T, Higashi S, Suzuki H, Eto S: Increased serum ferritin levels in adult Still's disease.

    Lancet 1987, 1:562-563. PubMed Abstract | Publisher Full Text OpenURL

  44. Van Reeth C, Le Moel G, Lasne Y, Revenant MC, Agneray J, Kahn MF, Bourgeois P: Serum ferritin and isoferritins are tools for diagnosis of active adult Still's disease.

    J Rheumatol 1994, 21:890-895. PubMed Abstract OpenURL

  45. De Benedetti F, Massa M, Pignatti P, Albani S, Novick D, Martini A: Serum soluble interleukin 6 (IL-6) receptor and IL-6/ soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis.

    J Clin Invest 1994, 93:2114-2119. PubMed Abstract | PubMed Central Full Text OpenURL

  46. Hoshino T, Ohta A, Yang D, Kawamoto M, Kikuchi M, Inoue Y, Kamizono S, Ota T, Itoh K, Oizumi K: Elevated serum interleukin 6, interferon-gamma, and tumor necrosis factor-alpha levels in patients with adult Still's disease.

    J Rheumatol 1998, 25:396-398. PubMed Abstract OpenURL

  47. Kawashima M, Yamamura M, Taniai M, Yamauchi H, Tanimoto T, Kurimoto M, Miyawaki S, Amano T, Takeuchi T, Makino H: Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still's disease.

    Arthritis Rheum 2001, 44:550-560. PubMed Abstract | Publisher Full Text OpenURL

  48. Gracie JA, Forsey RJ, Chan WL, Gilmour A, Leung BP, Greer MR, Kennedy K, Carter R, Wei X-Q, Xu D, Field M, Foulis A, Liew FY, McInnes IB: A proinflammatory role for IL-18 in rheumatoid arthritis.

    J Clin Invest 1999, 104:1393-1401. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  49. Bombardieri M, Pittoni V, Conti F, Spinelli FR, Spadaro A, Riccieri V, Alessandri C, Scrivo R, Valesini G: Reduction of IL-18 serum levels in rheumatoid arthritis during short term-treatment with infliximab [abstract].

    Ann Rheum Dis 2001, 60(suppl 1):99. OpenURL

  50. Fautrel B, Borget C, Rozenberg S, Meyer O, Le Loet X, Masson C, Kroeger AC, Kahn MF, Bourgeois P: Corticosteroid sparing effect of low dose methotrexate treatment in adult Still's disease.

    J Rheumatol 1999, 26:373-378. PubMed Abstract OpenURL

  51. Elliott MJ, Woo P, Charles P, Long-Fox A, Woody JN, Maini RN: Suppression of fever and the acute-phase response in a patient with juvenile chronic arthritis treated with monoclonal antibody to tumor necrosis factor-α (cA2).

    Br J Rhuematol 1997, 36:589-593. Publisher Full Text OpenURL

  52. Stambe C, Wicks IP: TNF-α and response of treatment-resistant adult-onset Still's disease to thalidomide.

    Lancet 1998, 352:544-545. PubMed Abstract | Publisher Full Text OpenURL

  53. Cavagna L, Caporali R, Epis O, Bobbio-Pallavicini F, Montecucco C: Infliximab in the treatment of adult Still's disease refractory to conventional therapy.

    Clin Exp Rheumatol 2001, 19:329-332. PubMed Abstract OpenURL

  54. Kraetsch HG, Antoni C, Kalden JR, Manger B: Successful treatment of a small cohort of patients with adult onset of Still's disease (AOSD) with infliximab: first experiences.

    Ann Rheum Dis 2001, 60(suppl 3):iii55-iii57. PubMed Abstract | Publisher Full Text OpenURL

  55. Villalba L, Adams EM: Update on therapy for refractory dermatomyositis and polymyositis.

    Curr Opin Rheumatol 1996, 8:544-551. PubMed Abstract OpenURL

  56. Tateyama M, Nagano I, Yoshioka M, Chida K, Nakamura S, Itoyama Y: Expression of tumor necrosis factor-alpha in muscles of polymyositis.

    J Neurol Sci 1997, 146:45-51. PubMed Abstract | Publisher Full Text OpenURL

  57. Kuru S, Inukai A, Liang Y, Doyu M, Takano A, Sobue G: Tumor necrosis factor-alpha expression in muscles of polymyositis and dermatomyositis.

    Acta Neuropathol 2000, 99:585-588. PubMed Abstract | Publisher Full Text OpenURL

  58. Kaklamani VG, Kaklamanis PG: Treatment of Behcet's disease – an update.

    Semin Arthritis Rheum 2001, 30:299-312. PubMed Abstract | Publisher Full Text OpenURL

  59. Mege JL, Dilsen N, Sanguedolce V, Gul A, Bongrand P, Roux H, Ocal L, Inanc M, Capo C: Overproduction of monocyte derived tumor necrosis factor alpha, interleukin (IL) 6, IL-8 and increased neutrophil superoxide generation in Behcet's disease. A comparative study with familial Mediterranean fever and healthy subjects.

    J Rheumatol 1993, 20:1544-1549. PubMed Abstract OpenURL

  60. Turan B, Gallati H, Erdi H, Gurler A, Michel BA, Villiger PM: Systemic levels of the T cell regulatory cytokines IL-10 and IL-12 in Bechcet's disease; soluble TNFR-75 as a biological marker of disease activity.

    J Rheumatol 1997, 24:128-132. PubMed Abstract OpenURL

  61. Sayinalp N, Ozcebe OI, Ozdemir O, Haznedaroglu IC, Dundar S, Kirazli S: Cytokines in Behcet's disease.

    J Rheumatol 1996, 23:321-322. PubMed Abstract OpenURL

  62. Calabrese L, Fleischer AB: Thalidomide: current and potential clinical applications.

    Am J Med 2000, 108:487-495. PubMed Abstract | Publisher Full Text OpenURL

  63. Travis SP, Czajkowski M, McGovern DP, Watson RG, Bell AL: Treatment of intestinal Behcet's syndrome with chimeric tumour necrosis factor alpha antibody.

    Gut 2001, 49:725-728. PubMed Abstract | Publisher Full Text OpenURL

  64. Sfikakis PP, Theodossiadis PG, Katsiari CG, Kaklamanis P, Markomichelakis NN: Effect of infliximab on sight-threatening panuveitis in Behcet's disease.

    Lancet 2001, 358:295-296. PubMed Abstract | Publisher Full Text OpenURL