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Anti-TNF therapy for other inflammatory conditions

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

1
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

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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.

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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).

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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,

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