Still's disease

Abstract

Etanercept is a dimeric fusion protein that has been approved for the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, active ankylosing spondylitis and moderate to severe plaque psoriasis. It has been reported to be useful in other variants of psoriasis, Still's disease, recurrent aphthous ulcers, and a variety of rare cutaneous conditions. Its cutaneous side effects are rare and include injection site reactions, cutaneous lupus, and cutaneous vasculitis. Its systemic side effects are also rare and include induction or worsening of infections, lupus, multiple sclerosis, and congestive heart failure. Linkage to an increased risk of lymphoma is unclear. In short, etanercept is a promising medication with substantial benefits and use will probably increase in the future. This review surveys off-label uses and side effects of etanercept.

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Introduction

Etanercept is a fusion protein administrated by subcutaneous injection consisting of the extracellular ligand-binding domain of the 75-kDa receptor for tumour necrosis factor alpha (TNF alpha or TNF[alpha]) and the constant domain of human IgG (1). It is effective because it blocks the activity of TNF[alpha], a cytokine crucial to the immune response and inflammation (1). Its activity is focused, and etanercept decreases inflammation but does not modify global production of immunoglobulins contributing to its safety (2). It has found a role in the treatment of a variety of inflammatory disorders.

Approved Uses

Etanercept currently has five indications from the Food and Drug Administration (FDA). It has been approved (1) to reduce the signs and symptoms and inhibit the structural damage in patients with moderately to severely active rheumatoid arthritis (RA); (3) to reduce the signs and symptoms of active arthritis in patients with psoriatic arthritis and may be used in combination with methotrexate or alone; (2) to reduce the signs and symptoms of moderately to severely active polyarticular-course juvenile rheumatoid arthritis (JRA) in patients who have had an inadequate response to disease-modifying medicines (4); (3) to treat psoriatic arthritis (5); (4) to treat active ankylosing spondylitis (6); and (5) moderate to severe plague psoriasis (7,8). This article will discuss etanercept's manifold uses for treating diseases aside from the diseases for which it is indicated to treat (9,10). This article will also review its side effects with particular attention to its role in dermatological therapy.

Treatment

Psoriasis and rheumatoid arthritis variants

Clinical trials for the use of etanercept have focused on treatment of the most common types of psoriasis and rheumatoid arthritis. However, etanercept has been reported to be useful in the treatment of types of psoriasis aside from moderate to severe stable plaque psoriasis and variants of rheumatoid arthritis and its associated symptoms. Still's disease, rheumatoid arthritis with fever and rash, can be responsive to etanercept (11,12). Etanercept has been found to be useful in treating generalized pustular psoriasis induced by cyclosporine withdrawal (13) and recalcitrant palmoplantar psoriasis (14).

Granulomatous diseases

The important role of TNF[alpha] in the functioning of macrophages and T-cells has suggested that blockage of the effects of TNF[alpha] would be helpful in treating granulomatous diseases. This has proven to be the case with infliximab, another TNF[alpha] blocker, but not etanercept. Whereas infliximab is an effective treatment of systemic Crohn's disease, etanercept does not seem useful in this regard. Subcutaneous etanercept at a dose of 25 mg twice weekly is safe, but not effective, for the treatment of patients with moderate to severe Crohn's disease (15). While not having an effect on Crohn's colitis, etanercept might have some effect though on the treatment of Crohn's related spondy-loarthritis (16). In patients with progressive stage II or III pulmonary sarcoidosis, etanercept was frequently associated with early or late treatment failure (17). Whereas etanercept has not been useful for treating pulmonary sarcoidosis, it has been reported to ameliorate sarcoidosis associated arthritis and skin disease (18). Lack of effect may be dose dependent.

Common variable immunodeficiency (CVI) is characterized by a failure in B-cell differentiation and impaired immunoglobulin secretion, but with a variable clinical presentation, including the development of sarcoidal granulomas and autoimmune diseases, as well as an increased incidence of malignancies. CVI has been treated effectively with etanercept (19).

Collagen vascular diseases

Etanercept's effectiveness in rheumatoid arthritis has suggested that it might be a useful treatment in other collagen vascular diseases. It has been investigated as a treatment for scleroderma and open label studies have been performed (20). Ellman reported 10 patients with diffuse scleroderma of less than 5 years duration who were treated for 6 months with etanercept 25mg twice weekly in addition to their existing treatment regime (21). In this study, one patient was removed from the study after 4 weeks due to worsening of finger ulceration. Four of the 9 patients who finished the trial showed marked improvement in their skin symptoms, while the other five showed no change. Etanercept has not been found to be a very effective treatment for Sjogren's syndrome although it might benefit subsets of patients (22).

Vasculitis

Because inflammation and vasculitis dovetail each other, observers have speculated that etanercept would be an effective treatment for vasculitis. Etanercept has been used with some effect in the treatment of Churg-Strauss syndrome refractory to cyclophosphamide and high dose glucocorticosteroid therapy (23). A study on its use in Wegner's granulomatosis is ongoing (24). Successful treatment of resistant giant cell arteritis has been reported (24). Interestingly, as will be discussed below, one of the main cutaneous side effects of etanercept is vasculitis.

Diseases in which Neutrophils Play an Important Role

Although TNF[alpha] is not the key cytokine underlying the function of neutrophils, its key role in inflammation would make it appear likely that blocking it would have some effect in diseases in which neutrophils play a role. Etanercept was found useful in the treatment of recalcitrant cicatricial pemphigoid, a blistering disease that commonly has neutrophils in its cutaneous infiltrate (26). Sustained response to etanercept in two patients with SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome has been reported (27). Recurrent aphthous ulcers (28) and recalcitrant, recurrent aphthous stomatitis (29) have been treated effectively with etanercept. It is interesting to note that thalidomide, which also works to block TNF-[alpha] is also an effective treatment for aphthous ulcers. Etanercept is, however, not always reported effective in neutrophilic disorders, and Behcet's syndrome responsive to infliximab after failure of etanercept has been noted (30). A recent report noted its utility in treatment of pemphigoid region.

Ophthalmological diseases

Rheumatoid arthritis can be accompanied by inflammation of the eye. Thus etanercept has been tested for the treatment of uveitis. Etanercept seems to both ameliorate and cause inflammation of the eye, so its role in treatment of uveitis is unclear (31). However, it can be an effective treatment for sight-threatening scleritis and sterile corneal ulceration (32).

Hematological diseases

Inflammatory mediators such as TNF[alpha] can be important in the propagation of malignancies, in particular those involving T-cells and macrophages and states of hemotological dysregulation. Thus, etanercept has been investigated as a treatment for hematological malignancies and states of hemoylogical dysregulation. Etanercept's use in the treatment of hematological malignancies is promising but has to be fully defined (33). Seven of eight patients with chronic graft versus host disease showed improvement with an 8-week course of etanercept (34). One report has noted that three patients with refractory immune thrombocytopenic purpura recovered completely after treatment with etanercept (35). In the treatment of myelodysplastic syndrome, etanercept treatment had mixed effects and resulted in moderate improvements of cytopenias in some patients, while cell counts declined in others (36). It was not effective for treating patients with refractory multiple myeloma (37).

Rare hematological diseases might benefit from treatment with etanercept. A case of Langerhans cell histiocytosis has been successfully treated with etanercept (38). In two patients with the hyperimmunoglobulinemia D and periodic fever syndrome, etanercept has been found helpful (39). Multicentric reticulohistiocytosis has been effectively treated with etanercept (40). Finally, etanercept can palliate constitutional symptoms in patients with myelofibrosis with myeloid metaplasia (41).

Amyloidosis

There appears to be a role for etanercept in the treatment of amyloidosis (42,43). With etanercept treatment there was resolution of nephrotic syndrome due to renal AA amyloidosis in adult Still's disease (44). In one study of etanercept for AL amyloid, 14 patients with AL amyloid were treated with etanercept for a median of 42 weeks, and 8 of 10 patients with cardiac amyloid remained stable with etanercept treatment; it was suggested in this study that the amyloid regression was due to 10% decrease in septal-wall thickness on echocardiography (45). Another study noted its utility in the treatment of advanced primary amyloidosis (46).

Pain

Because pain is associated with inflammation and TNF[alpha], etanercept is a promising treatment for pain resistant to conventional treatment. Etanercept, delivered by targeted subcutaneous injection, may be of benefit for selected patients with resistant pain associated with cervical disc disease (47). Etanercept can reduce pain and hyperalgesia in a mouse model of painful neuropathy, the chronic constriction injury of the sciatic nerve (48). Etanercept delivered by targeted subcutaneous injection may be of clinical benefit in selected patients with treatment-refractory pain caused by bone metastases (49).

Side Effects

Cutaneous side effects

A variety of cutaneous side effects have been rarely linked to etanercept. The most common of these are injection site reactions. Much more rare side effects include cutaneous lupus and cutaneous vasculitis.

Injection site reactions associated with etanercept therapy are not uncommon, and may be an example of a T-lymphocytemediated delayed-type hypersensitivity reaction, with waning over time due to eventual induction of tolerance (50,51). Such reactions can occur with the initial injections of etanercept (52). Such reactions have also been reported to develop with early injection site reactions that persisted and worsened into the tenth month of treatment with etanercept (53).

Several reports have linked etanercept to cutaneous vasculitis (84,85) and cutaneous lupus. One report noted two patients with such reactions to etanercept respectively (54). One patient was noted to have a patch of erythema with follicular hyperkeratosis at the injection site and other similar lesions at non-injection sites whose histology revealed discoid lupus-like lesions of folliculitis and in the other patient after the first injection, a single necrotic patch (5- X 7-cm) appeared on the right leg with a skin biopsy showing a necrotizing vasculitis and a monoclonal IgG cryoglobulinaemia was detected. There was no renal involvement in the later case. Another report of two patients noted cutaneous lupus and a necrotizing vasculitis with eosinophils (57). Etanercept has induced subacute cutaneous lupus erythematosus (58).

Rare cutaneous side effects with etanercept treatment have been reported. Single case reports have noted the development of rheumatoid nodules during treatment of rheumatoid arthritis with etanercept (59) and the development of atopic dermatitis with etanercept treatment (60). A patient with rheumatoid arthritis developed toxic epidermal necrosis after leflunomide and then erythema multiforme after etanercept treatment (61). Two patients with juvenile idiopathic arthritis during etanercept treatment developed an urticaria-like rash with prurigo appearing bilaterally on the extensor surfaces of the elbows subsequent to etanercept injections (62). Sarcoid-related uveitis has occurred during etanercept therapy (63).

Systemic side effects

A variety of systemic side effects have been rarely linked to etanercept. The most important of these include systemic lupus, central nervous system demyelination (64) and serious infection. Rare side effects have included aplastic anemia (65), lung injury (66), silent thyroiditis (67,68), and development of antibodies that interfere with monoclonal antibody laboratory assays (69). Etanercept's role in the induction of lymphoma is unclear in part because lymphoma is increased in both patients with psoriasis and rheumatoid arthritis (70).

Progression and development of congestive heart failure was linked to etanercept use, but most patients will experience an improvement or disappearance of the CHF after therapy is stopped but rarely patients can die (71). However in major trials of the use of etanercept for CHF only lack of efficacy in treatment of CHF was noted rather than worsening of CHF. Therefore, the trial for treatment of CHF was stopped. The reasons for the possible link between CHF and etanercept are unclear. This linkage was most substantially demonstrated in clinical trials in which patients with CHF were treated with etanercept and the CHF worsened in some cases (72). Some reports have suggested there is no link between CHF and etanercept use (73). It is possible that it is prudent to avoid using TNF[alpha] blockers in patients with CHF. New data gainsays the role of etanercept in worsening hearth disease (see below).

Rare reports have linked etanercept to the development of multiple sclerosis (74). The basis for its demyelinating effect is unclear. It appears preferable to avoid using it in patients with multiple sclerosis and appropriate testing should occur if a patient complains of symptoms that might be consistent with multiple sclerosis.

Reports have linked etanercept to increased autoantibody titers and lupus in a variety of contexts (75). Lupus has occurred in the context of treatment of rheumatoid arthritis with etanercept (76,77). Drug-induced systemic lupus erythematosus associated with etanercept therapy has occurred in a child with juvenile idiopathic arthritis (78) and in other contexts (79). The development of autoantibody titers might be a result of infections due to Staphylococcus aureus or Escherichia coli (80). Appropriate monitoring should occur in patients and when indicated autoantibodies should be checked in patients taking etanercept and when necessary the medication should be discontinued.

A common side effect of etanercept is the development of upper respiratory infections. Development of serious infections has occurred with treatment with etanercept (81) and the development of these is discussed in its package insert. These infections include listeria (82), histoplasmosis (83), and tuberculosis (84). Tuberculous tonsillitis (85) and mycobacteria tuberculosis peritonitis (86) have been noted in patients receiving etanercept treatment. Other reports have noted the development of viral pneumonia (87). There has been a report of a case of disseminated sporotrichosis in a 49-year-old man who was treated with multiple immunosuppressants, including etanercept and infliximab for arthritis (88). Etanercept has been linked to the development of toxoplasmosis (89). Multifocal septic arthritis and osteomyelitis caused by group A Streptococcus has occurred in a child receiving etanercept (90). Orbital myositis in a rheumatoid arthritis patient during etanercept treatment has been reported (91). It seems prudent to check a PPD and perform a comprehensive medical examination to ensure that infection is not present before starting etanercept.

Macrophage activation syndrome (MAS) is a serious complication of childhood systemic inflammatory disorders that is thought to be caused by excessive activation and proliferation of T lymphocytes and macrophages. MAS can be considered as secondary hemophagocytic lymphohistiocytosis and is a potentially life-threatening complication of systemic onset JRA (92). Etanercept has been used to treat MAS and has occurred after initiation of etanercept therapy in a child with systemic onset JRA (93).

It is unclear whether etanercept increase the incidence of cancer. One initial report linked the rapid onset of cutaneous squamous cell carcinoma in patients with rheumatoid arthritis treated with etanercept (94) However, a larger series did not find a linkage between etanercept and cutaneous squamous cell cancer (95). As stated above, it is unclear if there is an increased incidence of lymphoma in patients using etanercept (96). Incidentally, a case of acute myelogenous leukemia following etanercept therapy has been reported (97).

Recent Results on Heart Failure, Rheumatoid Arthritis and TNF[alpha] Blockers

Results comparing thousands of patients with rheumatoid arthritis using anti-TNF[alpha] therapy to those not using TNF[alpha] blockers (with patients with osteoarthritis not using TNF[alpha] blockers as controls) found that heart failure was increased in patients with rheumatoid arthritis as compared to osteoarthritis (3.9% vs 2.3%) and that patients with rheumatoid arthritis who used TNF[alpha] blockers had a decreased risk of heart failure as compared with those who did not use TNF[alpha] blockers (3.1% vs 3.8%). In the absense of pre-existing cardiovascular disease, the risk of heart failure was low (0.4% [24/6251]) and was not related to anti-TNF[alpha] therapy (98).

Conclusion

In conclusion, etanercept has found a variety of uses outside its four FDA-approved indications. Its utility in treating these conditions underlines the importance of TNF[alpha] in inflammatory disease. However, use of etanercept requires an awareness of its side effects. Basis for its linkage to the induction of multiple sclerosis, lupus and congestive heart failure is uncertain, but real and hence it should be used with care. The benefits of etanercept appear to outweigh its side effects and it is an effective medication that will yield manifold benefits to patients in the years to come.

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NOAH SCHEINFELD MD JD

DEPARTMENT OF DERMATOLOGY, ST. LUKE'S-ROOSEVELT HOSPITAL, NEW YORK, NY

ADDRESS FOR CORRESPONDENCE:

Noah Scheinfeld MD JD

Department of Dermatology

St Luke's-Roosevelt Hospital Center

1090 Amsterdam Ave. Suite 11B

New York NY 10025

Phone: (212) 523-3888

Fax: (212) 523-3808

E-mail: Scheinfeld@earthlink.net

COPYRIGHT 2004 Journal of Drugs in Dermatology, Inc.
COPYRIGHT 2005 Gale Group