You are on page 1of 6

Anti-TNF therapy for other inflammatory conditions

Z. Tutuncu1, G.J. Morgan, Jr.2, A. Kavanaugh1

The Center for Innovative Therapy, ABSTRACT lished studies confirm that anti-TNFα
Division of Rheumatology Allergy and The use of biolo gical agents in inflam - therapy can improve the signs and
Immunology, UCSD, School of Medicine, matory conditions is rapidly increas - symptoms of RA, retard the progres-
La Jolla, California; 2Division of Rheum-
ing. TNF blocking treatments have sion of joint erosions and joint space
atology, Dartmouth Hitchcock Medical
Center, Lebanon, New Hampshire, USA changed the course of rheumatoid narrowing and improve quality of life
arthritis, Crohn’s disease, juvenile (1-3).
Zuhre Tutuncu, MD, G. James Morgan,
Jr. MD, Arthur Kavanaugh, MD. rheumatoid arthritis and psoriatic Observations of improvement of coex-
arthritis. Open label studies with isting conditions (e.g. pyoderma gan-
Please address correspondence to:
Authur Kavanaugh, MD, 9310 Campus TNF inhibitors in other inflammatory grenosum or psoriasis in Crohn’s dis-
Point Drive, Suite A-111, La Jolla, CA conditions such as adult Still’s disease, ease), coupled with an accumulating
92037-0943, USA. uveitis, Wegener’s granulomatosis, body of information suggesting a role
Clin Exp Rheumatol 2002; 20 (Suppl. 28): Behçet’s disease, scleroderma, Sjö - for TNFα in the pathogenesis of other
S146-S151. gren’s syndrome, sarcoidosis, pyoder - immune mediated conditions has creat-
© Copyright CLINICAL AND EXPERIMEN- ma gangrenosum, polymyositis/derma - ed considerable enthusiasm for using
TAL RHEUMATOLOGY 2002. tomyositis have shown promising these and other biologic agents in pa-
results. However, whether anti-TNF tients with diverse diseases. Case re-
Key words: Anti-TNF therapy, therapy can be safely and efficaciously ports and small open-label studies have
inflammatory diseases applied to these other inflammatory revealed promising results, suggesting
disorders requires further controlled that anti -TNFα therapy may be a use-
studies. ful treatment option.

Introduction Adult Still’s disease

TNFα is considered one of the major Adult Still’s disease (AOSD) is a sys-
proinflammatory cytokines involved in temic inflammatory disorder of un-
the pathogenesis of many immune me- known etiology, characterized by high
diated disorders. Recently, two biolog- spiking fever, arthritis, neutrophilic
ical agents that inhibit TNFα have leukocytosis and transient cutaneous
become available: a soluble receptor rash. Even though the type of articular
antagonist (etanercept) and a chimeric involvement is distinct from RA, the
anti-TNFα monoclonal antibody long-term morbidity may similarly be
(mAb) (infliximab). The Food and dependent upon the chronicity and
Drug Administration (FDA) of the severity of arthritis. Of note, high ser-
United States has approved etanercept um levels of TNF have been demon-
and infliximab for use in the treatment strated during the acute phase of
of rheumatoid arthritis (RA); inflix- AOSD (4,5). Suppression of fever and
imab is also approved for use in refrac- the acute phase response in patients
tory and fistualizing Crohn’s disease; with JRA treated with anti- TNF mAb
and etanercept is approved for use in has provided supporting evidence for
juvenile rheumatoid arthritis (JRA), potentially using anti-TNFα therapy in
and psoriatic arthritis (PsA). AOSD (6).
RA is a systemic, inflammatory disor- In a pilot study, five AOSD patients
der characterized by symmetrical addi- received 25 mg etanercept twice week-
tive, erosive, and potentially deforming ly. All the patients showed improve-
arthritis. Joint inflammation leads to ment in fever, rash and joint pain/
erosive articular damage, which limits swelling within 3 weeks. Four of the
physical activities and reduces quality five patients completed 6-12 months of
of life. Over the past decade, advances therapy; they remained in clinical re-
in understanding the pathogenesis of mission with decreased prednisone
RA have led to the identification of a dosing (7). In a six-month open-label
number of noteworthy molecular tar- study, t we l ve patients with AOSD
gets; of these, therapy-targeting TNFα received 25 mg etanercept twice a
has been best validated. Recently pub- week or up to three times a week for

Anti-TNF therapy for other inflammatory conditions / Z. Tutuncu et al.

eight weeks. Eight of the patients Vasculitis BVAS/WG scores improved at the end
reached an ACR20 response, five out of The vasculitides constitute various cli- of six months, but intermittently active
twelve reached an ACR50, and two out nical and pathological syndromes, disease was observed in fifteen out of
of twelve reached ACR70 response. which create a therapeutic challenge. twenty patients (27). While early data
Only one of the three patients with Vasculitis is characterized by infiltra- are encouraging, definitive assessment
fever and rash had shown improvement tion of vessel walls by various cells of the efficacy of TNFα blockers in
in these symptoms. Tender and swollen including macrophages, and T lympho- WG will require controlled clinical tri-
joint count improved 54% and 63% re- cytes, with the production of many cy- als.
spectively (8). Six patients with AOSD tokines that are largely responsible for
were treated with 3 to 5mg/kg inflix- the signs and symptoms of the disease. Behçet’s disease
imab in an open label study at weeks 0, By immunohistochemical techniques, Behçet’s disease (BD) is a vasculitis of
2, 6 and then every 6 to 8 weeks. They TNFα has been demonstrated in up to unknown cause that is characterized by
were followed for 2 to 18 months. Res- 60% of the cells in all areas of inflamed recurrent genital and oral ulcers, skin
olution of fever, arthralgia, myalgia, temporal arteries of patients with giant lesions and ocular lesions. Arthritis,
splenomegaly and rash was noted in all cell arteritis (20). Although the effec- neurological and gastrointestinal mani-
patients (9). tiveness of biological agents in system- festations may also occur. A Th1-bias-
TNF blocking therapy appears to be ic vasculitis is unproven, their introduc- ed immune response seems to play a
well tolerated and improves articular tion may provide a new avenue for critical role in BD (28). TNFα and oth-
and systemic manifestations in AOSD. treatment. Cases of TNFα blockade er proinflammtory cytokines produced
Nevertheless, the long term effects and (infliximab) in giant cell arteritis have by monocytes may be an important part
optimal regimen of anti-TNF therapy is been reported (21). of the inflammatory cascade in BD
still to be determined. (29). The MHC class I molecule HLA-
Wegener’s granulomatosis B51 has been widely reported as a risk
Uveitis Wegener’s granulomatosis (WG) is factor for BD; HLA-C and TNF poly-
Uveitis is frequently associated with characterized by a multifocal inflam- morphisms have also been implicated
systemic inflammatory diseases. TNFα matory illness that most often affects (30,31). In a study of 102 patients with
has been implicated in the pathogenesis the upper and lower respiratory tracts ocular BD and 105 controls, a primary
of various forms of uveitis and has and kidneys. Evidence from a variety role for TNF gene polymorphism in
been extensively studied in several ani- of sources suggests that abnormal regu- BD was not identified, but co-expres-
mal models (10,11). An up-regulation lation of TNF may play a major role in sion of the TNFβ2 allele with HLA-
of the TNFα gene in the iris/cytoid WG. In animal models, granuloma for- B51 was found to contribute to the se-
body and high levels of TNFα in the mation, a classic pathological marker verity of the disease (32).
aqueous humor may contribute to intra- of WG, was markedly impaired by anti- Patients with refractory BD showing
ocular inflammation and parallel the bodies directed against TNF (22). Also, different system involvement have been
disease course (12). Mice lacking the transcription of the TNF gene has been treated with TNFα blockers. A patient
p55 and p75 TNF receptors develop shown to be enhanced in peripheral with recalcitrant orogenital ulceration
less ocular inflammation after chal- blood mononuclear cells from patients was treated with two doses of inflix-
lenge (13). However, there are contra- with WG (23). CD4+ T cells isolated imab (10 mg/kg) over one month. The
dictory reports about the effect of anti- from patients with WG produce elevat- patient’s symptoms dramatically im-
TNFα therapy on uveitis in rats. Dick ed levels of TNF (24). Serum levels of proved following the first infusion, and
et al. demonstrated that inhibition of soluble receptors for TNF are elevated he was still in remission twelve months
TNFα by the administration of a TNFα in patients with active WG, and nor- after the second infusion (33). In anoth-
receptor IgG fusion protein delayed the malize with remission (25). Studies of er case of orogenital ulcers, 5 mg/kg in-
onset and decreased the severity of renal biopsy tissue by immunohisto- fliximab infusions were given at weeks
uveitis in rats (14). In contrast, De Vos chemistry, polymerase chain reaction 0, 2, and 6 and the patient’s ulcers
et al. reported that anti-TNFα therapy and in situ hybridization from patients cleared for the first time in ten years
caused an exacerbation of endotoxin- with pauciimmune glomerulonephritis (34). Additional reports of patients with
induced uveitis in rats (15). confirm that TNF-positive cells infil- refractory ocular and gastrointestinal
Case reports regarding the use of TNFα trate histologically active renal lesions BD reveal that infliximab led to rapid
blockers in patients with inflammatory (26). In a six-month open-label study, and complete resolution of the patients’
uveitis are inconclusive. Although etanercept was well tolerated by pa- symptoms (17,18, 35, 36).
TNFα blockers help achieve remission tients with WG. Twenty patients were Given the significant morbidity and
in patients with certain subgroups of given 25 mg of etanercept twice a week limited success with current therapeu-
inflammatory eye disease (16-18), in addition to their standard therapies tic modalities in BD, the results of
some reports demonstrate insufficient for WG. The Birmingham Vasculitis these pilot studies support a rationale
response or even worsening of the Activity Score (BVAS/WG) was used for randomized controlled trials of TNF
symptoms (19). to determine the clinical response. blocking agents.

Anti-TNF therapy for other inflammatory conditions / Z. Tutuncu et al.

Scleroderma pancreas, sweat glands and renal tu- ESR, dry eyes and dry mouth. The
Progressive systemic sclerosis (SSc) is bules may also occur. treatment was well tolerated in all pa-
a connective tissue disease affecting TNFα expression in minor salivary tients, and no significant adverse events
various organs, including skin, gastro- gland duct cells in SS patients has been were seen (45).
intestinal tract, lung, kidney, and heart documented by many authors (40, 41).
with a primary fibrotic process often Animal models of SS also have shown Sarcoidosis
preceded by inflammation. The cause that PEGylated recombinant methionyl Sarcoidosis is a multisystem granulo-
of SSc is unknown; it is regarded as an human soluble TNF receptor I prevents matous disorder in which the cell-
autoimmune disease that involves cel- lymphocytic infiltration into lacrimal mediated immune response is activated
lular and humoral immunity. Cellular and salivary glands and blocks the by persistent exposure to one or more
infiltrates including CD4+, CD8+ T development of SS in the NOD mouse stimuli. Prolonged exposure leads to
cells, B cells, and macrophages have model (42). TNFα and IL-1β treated granulomatous inflammation that may
been demonstrated in various organs. normal human salivary cell clones with cause fibrosis and progressive organ
The mechanism of fibrosis in SSc is not acinar phenotype demonstrate high dysfunction most commonly in the
understood, although soluble mediators metalloproteinase activity in protein lung
such as transforming growth factor β, and mRNA levels. Further in vitro Many studies have confirmed elevated
platelet-derived growth factor, inter- studies demonstrated that blockade of TNFα production in sarcoidosis and
leukin (IL)-4, IL-6, TNFα can affect signal transduction pathways of TNFα have shown that TNFα plays an impor-
the behavior of fibroblast growth (37). or IL-1β can suppress cytokine-induc- tant role in granuloma formation (46,
It has also been shown that serum con- ed proteolytic enzyme activity (43). 47). There are also reports with incon-
centrations of soluble TNFα receptor These observations suggest that the di- sistent results about the role of TNF
type 1 (sTNFαR1) correlate with the vergent response to cytokines in sali- polymorphism in sarcoidosis. A higher
severity of the disease (38). There is vary gland may result in the histopatho- frequency of the uncommon TNFα2
still no single agent or combination logic manifestations of SS. It was also allele was found in patients with Loef-
therapy that has a clear impact on the shown that the balance of cytokines gren syndrome, which is an acute dis-
disease process or outcome. including TNFα in the tear fluid and ease resembling sarcoidosis (48). In a
In an open-label, single arm study of conjunctival epithelium is altered in SS different study, TNFα and β gene poly-
ten SSc patients, etanercept was admin- (44). In this study ELISA was used to morphisms have been investigated in
istered twice a week for six months detect the epidermal growth factor 26 patients with cardiac sarcoidosis.
(39). The Rodnan skin score was the (EGF) levels in tear fluid and RNA The results of this study showed that
primary outcome measure. It improved transcript levels encoding inflammato- there was a significant increase in
in four patients and did not change in ry cytokines. IL-6, IL-8, TNFα, trans- TNFα2 suggesting that the TNFα gene
five. One patient had experienced wor- forming growth factor β1 (TGF β1) may contribute to the genetic suscepti-
sening of fingertip ulcerations and dis- and housekeeping gene (G3PDH) were bility to cardiac sarcoidosis (49). How-
continued the study, while the others (n evaluated in conjunctival cytology ever, Yamaguchi et al. found no evi-
= 3) with digital ulcers showed im- specimens taken from 10 subjects with dence of TNFα gene polymorphism in-
provement. Pulmonary function tests SS and 10 healthy controls. EGF con- creasing the susceptibility to sarcoido-
remained stable through out the study. centration was decreased and the in- sis (50). In contrast to the other reports,
Patient and Physician Global Assess- flammatory cytokine levels were in- they found that the patients with allele
ment scores, and HAQ improved creased in the conjunctival epithelium TNF-β1 had a prolonged clinical
42.8%, 32.2%, and 12.7% respectively of the patients with SS compared to course. Different results might be relat-
compared to baseline. Oral aperture healthy controls. The severity of kera- ed to different patient populations or
and hand extension remained unchang- tokonjunctivitis sicca correlated with different forms of the disease.
ed. Still there are a lot of unknowns in high levels of inflammatory cytokine In a case report, three patients with
the pathophysiology of SSc. Further re- levels. These findings provide insight chronic, resistant sarcoidosis were
search needs to be conducted. into the pathogenesis of keratokonjunc- t re ated with infliximab 5 mg/kg at
tivitis and may open a therapeutic weeks 0, 2, 4 and 12 weeks. In two
Sjögren’s syndrome option in SS. patients the index lesion of lupus per-
Sjögren’s syndrome (SS) is a systemic In order to determine the short-term ef- nio significantly improved. The third
autoimmune attack on the exocrine sys- ficacy and safety of infliximab in pa- patient had restrictive lung disease,
tem characterized by dysfunction of the tients with primary SS, sixteen pa- which showed 26% improvement in the
lacrimal and salivary glands leading to tients, with active SS received three vital capacity from the baseline values
xerophtalmia and keratokonjunctivitis infusions of 3 mg/kg infliximab at 0, 2, (51). In a patient with sarcoidosis pre-
sicca. Histologically, it is characterized and 6 weeks. Patients were followed senting with protein-losing enteropa-
by the eventual total replacement of the for fourteen weeks. There was statisti- thy, and proximal myopathy, 5 mg/kg
acinar structure by marked lymphocyt- cally significant improvement in pa- infliximab infusion at weeks 0, 2 and 6
ic infiltrates. Infiltration of lung, liver, tient and physician global assessment, resulted in resolution of symptoms (52).

Anti-TNF therapy for other inflammatory conditions / Z. Tutuncu et al.

Pyoderma gangrenosum regarding the use of TNFα blockers in and consequently improving the patient
Pyoderma gangrenosum (PG) is a des- patients with many other autoimmune outcomes in autoimmune inflammatory
tructive inflammatory skin disease fre- diseases who have been refractory to conditions. TNFα inhibitors can be
quently associated with RA or inflam- traditional treatments. A case of hidra- safely added to other systemic agents
matory bowel disease, but can exist as denitis suppurativa occuring in a pa- to achieve better responses in some re-
an isolated lesion. PG develops in ap- tient with Crohn’s disease showed dra- calcitrant inflammatory diseases. The
proximately 3-5% of patients with ul- matic improvement after treatment range of disorders in which TNF α
cerative colitis and 1% of patients with with infliximab (58). Two patients with blockade may be beneficial need to be
Crohn’s disease. The lesions usually SAPHO syndrome (cluster of findings clearly identified in controlled trials. In
begin as small pustules but then ulcer- including synovitis, acne, palmoplantar addition, potential adverse effects of
ate. Subsequently, the lesions develop pustulosis, hyperostosis and osteitis, TNFα inhibition must be weighed
erythematous margins with inflamma- where the upper anterior chest wall is against potential clinical benefits. Fi-
tion, which undermines the edges. Dis- most commonly involved) presenting nally, the high cost of these agents also
turbances of immunoregulation and with chest pain limiting normal activity warrants careful patient selection.
immunologic effector functions are despite treatment with NSAIDs and One consideration relevant to the po-
involved in some patients with pyoder- second line therapies, received inflix- tential use of TNF inhibitors in condi-
ma gangrenosum; however no consis- imab (5 mg/kg) at weeks 0, 2, and 6. tions other than RA relates to the agents
tent pattern of disturbed cellular im- Signs and symptoms regarding SA- themselves; will clinically important
mune response has emerged. Treatment PHO syndrome disappeared and have differences in safety or efficacy be ob -
with immunosuppressive agents is not not reappeared two months after the served among the various TNF inhi-
always successful and may cause side last infusion (59). Graft-versus-host bitors ? Through 2002, there have been
effects. disease (GVHD) is recognized to be two TNF inhibitors approved for use
Two cases of PG with Crohn’s disease due to an immunologic reaction of en- worldwide; the chimeric anti-TNF-α
treated with infliximab had complete grafted lymphoid cells against the tis- monoclonal antibody (mAb) inflix-
resolution of most ulcers and this re- sues of the host; inflammatory cyto- imab, and the soluble p75 TNF-recep-
sponse lasted 2 to 2 1/2 months (53). kines may contribute to the tissue dam- tor IgG1-Fc fusion construct etaner-
age seen (60). In a number of pilot cept. In addition to sharing the ability
Polymyositis/dermatomyositis studies patients with acute or chronic to inhibit TNF, these molecules have
Polymyositis (PM) and Dermatomyosi- refractory GVHD were treated with other characteristics in common. Both
tis (DM) are inflammatory muscle dis- infliximab (62). The results of these are engineered macromolecules, with a
ease characterized clinically by sys- studies were encour aging, although in- volume of distribution that suggests
temic proximal muscle weakness, cuta- conclusive. Nevertheless, they justify largely intravascular distribution; both
neous lesions (in DM), and systemic further exploration of anti-TNF therapy are administered parenterally. Howev-
manifestations. Little is known about in GVHD. er, there are characteristics that vary
the ethiopathogenesis of these condi- Multicentric reticulohystiocytosis is a between these two agents. Monoclonal
tions. The role of pro-inflammatory cy- rare disorder of cutaneous nodules and antibodies are target specific, so anti-
tokines such as TNFα, IL-1 and IL-6 in arthritis which rapidly leads to joint TNF-α antibodies bind to TNF-α, but
PM/DM has not been clearly docu- destruction and generally is unrespon- not to the homologous cytokine lym-
mented. However, muscle biopsy spec- sive to therapy. Histologic analysis of photoxin-a (LT-α; previously known as
imens from PM/DM patients have skin and joint lesions reveals multinu- TNF-β). In contrast, soluble forms of
revealed that TNFα-positive macro- cleated giant cells and high levels of the TNF inhibitor bind both TNF-α and
phages and lymphocytes are expressed TNF. Treatment with TNF blockade LT-α. MAb efficiently bind both solu-
around blood vessels in tissue sections has been promising (two cases; Morgan ble and cell bound forms of TNF,
with myositis (54, 55). Levels of solu- personal communication). whereas the soluble receptor binds sol-
ble TNF receptor in peripheral blood The treatment of the autoinflammatory uble cytokine more efficiently. While
mononuclear cells from patients with syndrome TRAPS (TNF-receptor asso- both compounds bind their target with
active-stage PM/DM were also demon- ciated periodic syndrome) has also high affinity, the avidity of the mAb
strated to be elevated compared to nor- been reported with TNF blockade (62). binding to target may be greater.
mal controls and inactive patients with In this syndrome abnormal shedding of Although the half lives of the currently
PM/DM (56). In a report of 2 cases TNF receptors leads to increased in- available agents are similar (etanercept
treated with infliximab, improvement flammatory response and this can be ~ 4.5 days, infliximab ~ 9.5 days),
in strength correlated with a decrease in blocked with anti-TNF therapy. inflximab is administered intravenous-
muscle fiber inflammation and necrosis ly and has a large peak post-dosing fol-
(57). Conclusion lowed by a steady state, whereas etan-
There is no doubt that anti-TNFα treat- ercept is administered subcutaneously
Case reports ment provides a major advance in bet- and achieves a steady state without a
Anecdotal data has been published ter targeting the inflammatory response large peak after several days. Finally,

Anti-TNF therapy for other inflammatory conditions / Z. Tutuncu et al.

mAb tend to be more efficient at effect- 4. HOSHINO T, OHTA A, YANG D et al.: Elevat- Lancet 2001; 358: 295-6.
ed serum Interleukin 6, Interferon-δ, and 18. MUNOZ-FERNANDEZ S, VENTURA H, FER-
ing activities through their Fc piece, for
tumor necrosis factor-α levels in patients NANDEZ-MELON J, SCHLINKER A, MAR-
example cell lysis and induction of with adult Still’s disease. J Rheumatol 1998; TIN-MOLA E: Effect of infliximab on threat-
apoptosis, although the extent to which 25: 396-8. ening panuveitis in Behçet’s disease. Lancet
this occurs in vivo is not certain. Whe- 5. FUJII T, NOJIMA T, YASUOKA H et al.: Cy- 2001; 358: 644:5.
tokine and immunogenetic profiles in Japa- 19. REIFF A,SYUJI T, SADEGHI S et al.: Etaner-
ther these differences will result in nese patients with adult Still’s disease. Asso- cept therapy in children with treatment-resis-
variable efficacy or safety remains to ciation with chronic articular disease. Rheu - tant uveitis. Arthritis Rheum 2001; 44:1411-
be determined for the various diseases matology 2001; 40: 1398-404. 5.
in which TNF inhibition has been tried. 6. ELLIOTT MJ, WOO P, CHARLES P, LONG- 20. FIELD M, COOK A, GALLAGHER G: Immu-
FOX A, WOODY JN, MAINI RN : Suppression no-localisation of tumor necrosis factor and
Of note, several other inhibitors of TNF of fever and the acute-phase response in a its receptors in temporal arteritis. Rheumatol
in various stages of clinical develop- patient with juvenile chronic arthritis treated Int 1997; 17: 113-8.
ment may be introduced in the future. with monoclonal antibody to tumour necrosis 21. CANTINI F, NICCOLI L, SALVARANI C,
Some are macromolecules, including factor-α (cA2). Br J Rheumatol 1997; 36: PADULA A, OLIVIERI I: Treatment of long-
589-93. standing active giant cell arteritis with inflix-
the human anti-TNF-α mAb adali- 7. TAMESIS ER, REGINATO AM, HUBSCHER O , imab: report of four cases. Arthritis Rheum
mumab (previously known as D2E7), CAMDEN AJR: Etanecept in recalcitrant 2001; 44: 2933-5.
the PEGylated human anti-TNF-α adult onset Still’s disease (AOSD). Arthritis 22. KINDLER V, SAPPINO AP, GRAU GE,PIGUET
mAb Fab’ fragment CDP870, and a Rheum 2000; 43: S229. PF, VASSALLI P : The inducing role of tumor
8. WEINBLATT ME, MAIER AL, OVERMAN SS, necrosis factor in the development of bacteri-
PEGylated soluble p55 TNF receptor MEASE P, FRASER PA, GRAVALLASE EM : cidal granulomas during BCG infection. Cell
construct. A variety of other strategies Etanercept in Still’s disease in the adult. 1989; 56: 731-40.
are also being tested with the ultimate Arthritis Rheum 2000; 43: S391. 23. DEGUCHI Y, SHIBATA N , KISHIMOTO S: En-
9. KRAETSCH HG, ANTONI C, KALDEN JR, hanced expression of the tumor necrosis fac-
goal of inhibiting the function of TNF,
MANGER B: Successful treatment of a small tor/cachectin gene in peripheral blood mo-
including p38-MAPkinase inhibitors cohort of patients with adult onset of Still nonuclear cells from patients with systemic
and NF-κB inhibitors. While novel, the disease with infliximab. Arthritis Rheum vasculitis. Clin Exp Immunol 1990; 81: 311-
macromolecule TNF inhibitors might 2001; 44: S118. 4.
be predicted to have many characteris- Expression of multiple cytokines and IL- Active Wegener’s granulomatosis is associat-
tics similar to the current TNF inhi- 1RA in the uvea and retina during endotoxin- ed with HLA-DR+ CD4+ T cells exhibiting
bitors. However, the small molecule ki- induced uveitis in the rat. Invest Ophtalmol an unbalanced Th1-type T cell cytokine pat-
nase inhibitors in development may be Vis Sci 1994; 35: 3873-83. tern: Reversal with IL-10. J Immunol 1998;
11. NAKAMURA S, YAMAKAWA T, SUGITA M et 160: 3602-9.
found to possess characteristics quite al.: The role of tumor necrosis factor-alpha in 25. NASSANOW E,SAMSONOW M,TILZ G et al.:
distinct from current agents. The im- the induction of experimental autoimmune Serum concentrations of neopterin, soluble
pact of these differences on potential uveoretinitis in mice. Invest Ophtalmol Vis interleukin 2 receptor, and soluble tumor ne -
efficacy and tolerability remains to be Sci 1994; 35: 3884-9. crosis factor receptor in Wegener’s granulo-
12. OKADA AA, SAKAI J, USUI M, MIZUGUCHI matosis. J Rheumatol 1997; 24: 666-70.
seen. J: Intraocular cytokine quantification of ex- 26. NORONHA I, KRUGER C, ANDRASSY K,
The future challenge for us is to design perimental autoimmune uveoretinitis in rats. RITZ E, WALDHERR R: In situ production of
clinical trials that will allow us to dis- Ocul Immunol Inflamm 1998; 6: 111-20. TNF-alpha, IL-1 beta and IL-2R in ANCA-
cover the unknown about the optimal 13. BRITO BE,O’ROURKE LM, PAN Y, ANGLIN J, positive glomerulonephritis. Kidney Int 1993;
PLANCK SR, ROSENBAUM JT: IL-1 and 43: 682-92.
usage, long-term benefits, and safety of TNF receptor-deficient mice show decreased 27. STONE JH, MISTY L, UHLFELDER ML et al.:
TNFa blockers in patients with various inflammation in an immune complex model Etanercept combined with conventional
inflammatory disorders. Although of uveitis. Invest Ophtalmol Vis Sci 1999; 40: treatment in Wegener’s granulomatosis.
2583-9. Arthritis Rheum 2001; 44: 1149-54.
there are many questions to be answer-
ed, these biological agents will serve as al.: Inhibition of tumor necrosis factor activi- CHIONE T : Immunopathological aspects of
a new hope in the management of ty minimizes target organ damage in experi- Behçet’s Disease (editorial). Clin Exp Rheu -
refractory inflammatory conditions. mental autoimmune uveoretinitis despite matol 1995; 13: 687-91.
quantitatively normal activated T cell traffic 29. MEGE JL, DILSEN N, SANGUEDOLCE V et
to the retina. Eur J Immunol 1996; 26: 1018- al.: Overproduction of monocyte derived
References 25. tumor necrosis factor alpha, interleukin (IL)
1. WEINBLATT ME, KREMER JM, BANKHURST 15. D E VOSAF, VAN HAREN MA,VERHAGEN C, 6, IL-8 and increased neutrophil superoxide
AD et al.: A trial of etanercept,a recombinant HOEKZEMA R, KIJLSTRA A: Systemic anti- generation in Behçet’s disease. A compara-
tumor necrosis factor receptor:Fc fusion pro- tumor necrosis factor antibody treatment tive study with familial Mediterranean fever
tein, in patients with rheumatoid arthritis exacerbates endotoxin-induced uveitis in the and healthy subjects, J Rheumatol 1993; 20:
receiving methotrexate. N Eng J Med 1999; rat. Exp Eye Res 1995; 61: 667-75. 1544:9.
340: 253-9. 16. SMITH JR, LEVINSON RD , HOLLAND GN et 30. MIZUKI N , OHNO S: Immunogenetic studies
2. LIPSKY PE, VAN DER HEIDJE DMFM, WIL- al.: Differential efficacy of tumor necrosis of Behçet’s disease. Rev Rheum 1996; 63:
LIAM SCE et al.: Infliximab and Methotrex- factor inhibition in the management of in- 520-7.
ate in the treatment of rheumatoid arthritis. N flammatory eye disease and associated rheu- 31. SANS L, GONZALES-ESCRIBANO MF, DE
Engl J Med 2000; 343: 1594-602. matic disease. Arthritis Rheum 2001; 45: PABLO R, NUNEZ-ROLDAN A, KREISLER M,
3. BATHON JM, MARTIN RW, FLEISCHMAN 252-7. VILCHES C: HLA-Cw1602:A new suscepti-
RM et al.: A comparison of etanercept and 17. SFIKAKIS PP, THEODOSSIADIS PG, KAT- bility marker of Behçet’s disease in southern
methotrexate in patients with early rheuma - SIARI CG, KAKLAMANIS P, MARKOMICHE- Spain. Tissue Antigens 1998;51:111-4.
toid arthritis. N Eng J Med 2000; 343: 1586- LAKIS NN: Effect of infliximab on sight- 32. VERITY DH, WALLACE GR, VAUGHAN RW
93. threatening panuveitis in Behçet’s disease. et al.: HLA and tumour necrosis factor

Anti-TNF therapy for other inflammatory conditions / Z. Tutuncu et al.

(TNF) polymorphisms in ocular Behçet’s 43. AZUMA M, KEIKO A, TETSUYA T et al.: GEORGE J , LEBWOHL MG : Improvement of
disease. Tissue Antigens 1999; 54: 264-71. Suppression of tumor necrosis factorα-in- pyoderma gangrenosum and psoriasis associ-
33. GOSSENS PH, VERBURG RJ, BREEDVELD duced matrix metalloproteinase 9 production ated with Crohn’s disease with anti-tumour
FC: Remission of Behçet’s syndrome with by the introduction of a super-repressor form necrosis factor α monoclonal antibody. Ar -
tumour necrosis factor α blocking therapy. of inhibitor of nuclear factor kBα comple- chives Dermatol 2001; 1377: 930-3.
Ann Rheum Dis 2001; 60: 637. mentary DNA into immortalized human sali- 54. LUNDBERG I, ULFGREN AK, NYBERG P,
34. ROBERTSON LP, HICKLING P: Treatment of vary gland acinar cells. Arthritis Rheum ANDERSSON U, KLARESKOG L: Cytokine
recalcitrant orogenital ulceration of Behçet’s 2000; 43: 1756-67. production in muscle tissue of patients with
syndrome with infliximab. Rheumatology 44. PFLUGFELDER SC, JONES D, JI Z, AFONSO idiopathic inflammatory myopathies. Arthri -
2001; 40: 473-4. A, MONROY D: Altered cytokine balance in tis Rheum 1997; 40: 865-74.
35. HASSARD PV, BINDER SW, NELSON V, the tear fluid and conjunctiva of patients with 55. TATEYAMA M, NAGANO I, YOSHIOKA M,
VASILIAUSKAS EA: Anti-tumor necrosis fac- Sjögren’s syndrome keratokonjunctivitis sic- CHIBA K, NAKAYAMA S, ITOYAMA Y: Ex-
tor monoclonal antibody therapy for gas- ca. Curr Eye Res 1999; 19: 201-11. pression of tumor necrosis factor-α in mus-
trointestinal Behçet’s disease: A case report. 45. STEINFELD SD, DEMOLS P, SALMON I,KISS cles of polymyositis. J Neurol Sci 1997; 146:
Gastroenterology 2001; 120: 995-9. R, APPELBOOM T : Infliximab in patients 45-51.
36. TRAVIS SP, CZAJKOWSKI M, MC GOVERN with primary Sjögren’s syndrome. A pilot 56. SHIMIZU T, TOMITA Y, SON K, NISHINARITA
DP, WATSON RG, BELL AL : Treatment of study. Arthritis Rheum 2001; 2371-5. S, SAWADA S, HORIE T: Elevation of solu-
intestinal Behçet’s syndrome with chimeric 46. BERGERON A, BONAY M, KAMBOUCHNER ble serum tumour necrosis receptors in pa-
tumour necrosis factor alpha antibody. Gut M et al.: Cytokine patterns in tuberculous and tients with polymyositis and dermatomyosi-
2001; 49: 725-8. sarcoid granulomas: Correlations with histo - tis. Clin Rheumatol 2000; 19: 352-9.
37. SAPADIN AN, FLEISCHMAJER R: Treatment pathologic features of the granulomatous re- 57. HENGSTMAN G, VAN DEN HOOGEN F, VAN
of scleroderma. Arch Dermatol 2002; 138: sponse. J Immunol 1997; 159: 3034-43. ENGELEN B et al.: Anti-TNF-blockade with
99-105. 47. BACHWICH RP, LYNCH JP, LARRICK L et al.: infliximab (remicade) in polymyositis and
38. MAJEWSKI S, WOJAS-PELC A, MALEJCZYK Tumor necrosis factor production by human dermatomyositis. Arthritis Rheum 2000; 43
M, SZYMANSKA E, JABLONSKA S : Serum sarcoid alveolar macrophages. Am J Pathol (Suppl. 9): s193.
levels of soluble TNF α receptor type 1 and 1986; 15: 421-5. 58. MARTINEZ F, NOS P, BENLLOCH S, PONCE
the severity of systemic sclerosis. Acta Derm 48. SEITZER U, SWIDER C, STUBER F et al.: J: Hidradenitis suppur ativa and Crohn’s dis-
Venereol (Stockh) 1999; 79: 207-10. Tumor necrosis factor-α promotor gene poly- ease: Response to treatment with infliximab.
39. ELLMAN MH, MACDONALD PA, HAYES FA: morphisms in sarcoidosis. Cytokine 1997; 9: Inflamm Bowel Dis 2001; 7: 323-6.
Etanercept as treatment for diffuse scleroder- 787-90. 59. OLIVIERI I, PADULA A, CIANCIO G, SAL-
ma:A pilot study. Arthritis Rheum 2000; 43: 49. TAKASHIGE N, NARUSE TK, MATSUMORI VARANI C, NICCOLI L, CANTINI F: Success-
s392. A et al.: Genetic polymorphism at the tumour ful treatment of SAPHO syndrome with in-
40. BOUMBA D, SKOPOULI FN, MOUTSOPOU- necrosis factor loci (TNFα and TNFβ) in car- fliximab: Report of two cases. Ann Rheum
LOS HM : Cytokine mRNA expression in the diac sarcoidosis. Tissue Antigens 1999; 54: Dis 2002: 61: 375-6.
labial salivary gland tissues from patients 191-5. 60. COURIEL DR, HICKS K, GIRALT S, CHAM-
with primary Sjögren’s syndrome. Br J Rheu - 50. YAMAGUCHI E, ITOH A, HIZAWA N , KAWA- PLIN RE: Role of tumor necrosis factor-alpha
matol 1995; 34: 326-33. KAMI Y : The gene polymorphisms of tumor inhibition with infliximab in cancer therapy
41. FOX RI,KANG HI,ANDO D, ABRAMS J, PISA necrosis factor-β, but not that of tumor necro- and hematopoietic stem cell transplantation.
E: Cytokine mRNA expression in salivary sis factor-α is associated with the prognosis Curr Opin Immunol 2000; 12: 582-7.
gland biopsies of Sjögren’s syndrome. J Im - of sarcoidosis. Chest 2001; 119: 753-61. 61. HERVE P, FLESCH M, TIBERGHIEN P et al.:
munol 1994; 152: 5532-9. 51. BAUGHMAN RP, LOWER EE: Infliximab for Phase I-II trial of a monoclonal anti-tumor
42. TORNWALD J, FOX H, EDWARDS C, FOX RI: refractory sarcoidosis. Sarcoidosis Vasc Dif - necrosis factor alpha antibody for the treat-
Treatment with pegylated recombinant mr- fuse Lung Dis 2001; 18: 70-4. ment of refractory severe acute g raft-versus-
thionyl human soluble tumor necrosis factor- 52. YEE AM, POCHAPIN MB : Treatment of com- host disease. Blood 1992; 79: 3362-8.
type! receptor (PEG sTNF-R1) prevents dev- plicated sarcoidosis with infliximab anti- 62. GALON J, AKSENTIJEVICH I, M CDERMOTT
elopment of Sjögren’s syndrome and diabe- tumour necrosis factor-alpha therapy. Ann MF, O'SHEA JJ, KASTNER PL: TNFRSFIA
tes in the NOD mouse model. A rt h ri t i s Intern Med 2001; 135: 27-31. mutations and autoinflammatory syndromes.
Rheum 1999; 42 (Suppl. 9): S403. 53. TAN MH, GORDON M, LEBWOHL O, Curr Opin Immunol 2000; 12: 479-86.