TNF inhibitors

The biologic effects of T cell–derived and monocyte-derived cytokines can explain much of the clinical syndrome of synovitis as well as the systemic manifestations associated with JIA. Cytokines are critical in perpetuating and damping the immune response, and as such they are important targets for therapeutic manipulation. TNF inhibitors have now been proven to be effective in the treatment of a number inflammatory conditions, including polyarticular course JIA, psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease ( Table 13-2 ).

Anti-TNF agents currently in use or under study in children are etanercept, infliximab, adalimumab, golimumab, and certolizumab ( Table 13-2 ).

Etanercept

Etanercept is a fully human, dimeric protein containing the extracellular domain of the human p75 TNF receptor fused to the Fc region of human IgG1. By binding to trimers of TNF-α in the circulation, etanercept prevents the interaction of TNF-α with its cell surface receptor, thereby preventing cell activation and perpetuation of the inflammatory cascade. It can also modulate biologic responses that are mediated by TNF, such as expression of adhesion molecules, serum concentration of matrix metalloproteinases (MMPs), and cytokines. Although soluble forms of the TNF-α receptor occur naturally, they are generally inadequate to block TNF activity in systemic inflammatory disorders. The dimeric form of the TNF-α receptor is much more efficient at binding TNF because it binds at a much greater affinity (50 to 1000 times higher) than that of the naturally occurring form. Etanercept also binds lymphotoxin (formerly called TNF-β). The role of lymphotoxin in the pathogenesis of arthritis is not as well understood as that of TNF-α. The half-life of etanercept, administered subcutaneously, is approximately 4 days. Etanercept was initially given twice weekly but is as effective using the same total dose once a week. In adults with RA, steady-state concentrations are achieved in about 2 weeks. Etanercept has been used extensively in children with JIA since the initial report of its effectiveness in 2000. It is currently indicated for children age 2 and above for polyarticular JIA in both North America and Europe. In Europe it is also approved for use in children ages 12-17 with psoriatic arthritis or enthesitis-related arthritis. A study of nearly 600 subjects demonstrated its relative safety over 3 years. Long-term continuous treatment up to 10 years appears to be safe with little evidence of tachyphylaxis. Guidelines for the use of etanercept are shown in Table 13-9 .

To date, etanercept has been very well tolerated. The placebo-controlled study showed an increase in symptoms of upper respiratory tract infection as well as injection site reactions, although these were generally mild. Injection site reactions may be treated with topical corticosteroids. However, postmarketing studies have reported a variety of unusual side effects; most importantly, systemic infection must be closely watched for. This includes bacterial infection, viral infection such as varicella with or without superimposed bacterial infection, and granulomatous infection. Although these infections are more common in elderly patients, physicians must be attuned to their development in any age group. Two patients in the pivotal trial developed aseptic meningitis secondary to varicella zoster, prompting the recommendation that JIA patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to starting etanercept. Patients with a significant exposure to varicella virus should temporarily discontinue etanercept and be considered for prophylaxis with varicella zoster immune globulin. Live virus vaccination is contraindicated, but concurrent methotrexate and etanercept did not appear to decrease the rate of seroconversion to MMR vaccination.

A variety of other side effects have been noted. Although rare enough to be the subject of case reports, there may be an association between treatment with etanercept and the development of vasculitic skin rash, and systemic or drug-induced lupus. The associations with pancytopenia and aplastic anemia are less clear. Several cases of diabetes mellitus after etanercept treatment have been reported in children with JIA. Patients experiencing changes in mood, weight gain, autoimmune hepatitis, thymic enlargement, sterile cholecystitis, tuberculous uveitis, and macrophage activation syndrome while being treated with etanercept have been reported.

Infliximab

Infliximab is a chimeric anti–TNF-α antibody consisting of a mouse Fab′ fragment antibody and the constant region of the human IgG1. In contradistinction to Cepts such as etanercept, monomers of infliximab bind not only to monomers of soluble TNF-α but also to membrane-bound TNF-α, leading to both antibody-dependent and complement-dependent cytotoxicity. It seems to be more efficacious than etanercept in granulomatous inflammatory disorders (e.g., sarcoidosis) and uveitis but also seems to be associated with the development of granulomatous opportunistic infections. Administration of infliximab is through the intravenous route ( Table 13-10 ). Dose and frequency vary somewhat with the clinical response. Initial doses in adults usually start at 3 mg/kg and are given at time 0, at 2 weeks, at 6 weeks, and then every 8 weeks depending on clinical response. Starting doses in children should be 6 mg/kg routinely (see the next paragraph). Doses often require escalation, and doses up to 20 mg/kg have been used occasionally in children. Alternatively, the length of time between infusions can be shortened. Administration with methotrexate (MTX) is recommended to prevent the development of anti-infliximab antibodies, which seem to correlate with infusion reactions and accelerated clearance of infliximab. It is not certain, however, that these antibodies actually reduce the effectiveness. Similar to etanercept, combination treatment with MTX seems to improve the response to infliximab in patients with RA.

Ruperto et al. reported the results of a randomized, double-blind, placebo-controlled trial of infliximab in patients with polyarticular-course JIA. The clearance of the drug was more rapid in children with juvenile rheumatoid arthritis (JRA) than was observed in adults with RA, resulting in lower trough levels before the next dose. Infliximab was generally well tolerated, but the safety profile of infliximab at a dose of 3 mg/kg appeared less favorable than that of infliximab at a dose of 6 mg/kg, with more frequent occurrences of serious adverse events, infusion reactions, antibodies to infliximab, and newly induced antinuclear antibodies and antibodies to double-stranded DNA observed with the 3 mg/kg dose, perhaps related to the lower trough levels in the 3-mg/kg group.

Treatment with infliximab resulted in reduced serum concentrations of interleukin (IL)-6, myeloperoxidase, and soluble adhesion molecules ICAM-1, and E-selectin. TNF-α levels tended to increase while the concentrations of endogenous TNF antagonists (sTNF-RI and sTNF-RII) were reduced.

Infection remains the major concern with the use of infliximab. Many more cases of tuberculosis have been reported in patients treated with infliximab than in those treated with etanercept, probably because of the destabilization of previously formed granulomata. Other infections that have occurred with greater than expected frequency include histoplasmosis, coccidioidomycosis, and listeriosis. One case of optic neuritis has been reported in a child. IgA and IgM anti-double-stranded DNA antibodies can occur with infliximab therapy, but only 1 of 156 patients with these antibodies developed lupus. In addition to the side effects noted with etanercept, infusion reactions ranging from mild allergic reactions to anaphylactic reactions may occur, more commonly on the second or third infusions. Therefore, infliximab must be administered under close observation. See Table 13-10 for guidelines regarding administration.

Adalimumab

Adalimumab is a recombinant human IgG1 mAb that acts in a similar fashion to infliximab and golimumab by binding to the TNF both in the circulation and on the cell surface. Therefore, it may result in cell lysis in the presence of complement. Adalimumab, but not etanercept, has been shown to induce immunosuppressive T _reg cells. It is administered subcutaneously with a half-life of approximately 2 weeks. Initial recommended dosing in children was 24 mg/m ² every second week. In North America the tendency is to administer 20 mg every second week for patients weighing less than 30 kg, and 40 mg every second week for patients weighing more than 30 kg. As with other anti-TNF agents, the effects are seen quickly, but the dose may need to be given once a week for sustained improvement. Injection site reactions can be problematic. Some practitioners add lidocaine into the syringe. The combination of adalimumab and MTX is safe and results in increased efficacy in RA.

A pivotal study resulted in FDA approval for the use of adalimumab for polyarticular JIA. ( Table 13-11 ). Serious adverse events possibly related to adalimumab occurred in 14 patients; 7 of these patients had serious infections (bronchopneumonia, herpes simplex virus infection, pharyngitis, pneumonia, viral infection, and 2 cases of herpes zoster). Twelve patients discontinued treatment because of adverse events. No deaths, malignant conditions, opportunistic infections, tuberculosis, demyelinating diseases or lupuslike reactions occurred. Sixteen percent of patients (6% on MTX; 26% not on MTX) had at least one positive test for anti-adalimumab antibodies. Development of anti-adalimumab antibodies did not affect the incidence of serious adverse events.

Golimumab

Golimumab is a recombinant human IgG monoclonal antibody to TNF-α. The constant regions of the heavy and light chains of this monoclonal antibody are identical in amino acid sequence to the corresponding constant regions of the human–mouse chimeric mAb infliximab. However, in contrast to infliximab, the heavy and light variable regions are of human sequence. The recommended dosage is 50 mg subcutaneously once a month in combination with MTX. The FDA approved golimumab in 2009 for the treatment of moderately to severely active adult RA, psoriatic arthritis, and ankylosing spondylitis. In the pivotal trial, one patient died after developing nausea, diarrhea, ileus, aspiration pneumonia, and sepsis. The most frequent adverse events were infection and injection site reaction. Antinuclear antibodies may occur, and their development may correlate with higher doses of golimumab or the absence of MTX. Antibodies to golimumab were observed in 2.1% of the subjects and were not significantly associated with decreased efficacy or injection site reaction. Pediatric studies are under way, but there are no published pediatric data to date.

Certolizumab

Certolizumab pegol is a pegylated (i.e., conjugated with polyethylene glycol) humanized Fab′ fragment of a monoclonal antibody that binds TNF-α. Pegylation increases its half-life. As opposed to infliximab, adalimumab, and golimumab—which are full-length bivalent IgG mAbs—certolizumab is a monovalent Fab antibody fragment. It has a higher affinity for TNF-α, is devoid of the Fc portion of the antibody, and does not induce complement activation, antibody-dependent cellular cytotoxicity, or apoptosis. Its efficacy and safety in active RA have now been assessed in three phase III, multicenter, randomized, double-blind, placebo-controlled clinical trials. In the most recent study of 619 subjects, certolizumab pegol plus MTX were more efficacious than placebo plus MTX, rapidly and significantly improving signs, symptoms, and physical function in patients with RA, and inhibiting radiographic progression. The dose was 200 mg or 400 mg subcutaneously every 2 weeks. Five patients developed tuberculosis. Pediatric studies are under way.

Common issues with anti-TNF agents

With the increasing use of anti-TNF agents, a number of common concerns have arisen, one of which is the increased risk of infection, particularly tuberculosis; fungal infections, including histoplasmosis; and other opportunistic infections. Children with JIA had a higher rate of opportunistic infections, including an increased rate of coccidioidomycosis, salmonellosis, and herpes zoster. Among children with JIA, the rate of infection was not increased with MTX or TNF-inhibitor use but was significantly increased with high doses of corticosteroids. In general, before starting treatment with any of these agents, the following approach is recommended: patients should be screened for the presence of latent tuberculosis with a tuberculosis skin test or a blood-based diagnostic assay (e.g., Quantiferon-Gold). The latter may have higher specificity particularly in patients who have had bacillus Calmette-Guérin (BCG) vaccination. A chest radiograph is probably unnecessary unless the purified protein derivative (PPD) result is positive. If the skin test or blood-based assay is positive, thorough investigation of the patient and family for active tuberculosis must be undertaken, and the patient must be treated accordingly. If the investigations prove negative, the patient should be given isoniazid (INH). Treatment with anti-TNF agents may be initiated 1 month after starting INH, although some give INH simultaneously with TNF-inhibitor therapy. The FDA advises close monitoring of patients for signs and symptoms of potential fungal infection, especially in endemic areas, both during and after treatment with anti-TNF drugs. Patients in whom fever, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates on chest radiographs, or serious systemic illness develop should undergo a complete diagnostic workup appropriate for immunocompromised patients. The decision to initiate empiric antifungal therapy in at-risk symptomatic patients should be made in conjunction with an infectious diseases specialist, taking into account both the risk for severe infection and the risks of antifungal therapy. TNF inhibitors should be withheld for serious infection or sepsis. Anti-TNF treatment should not be used in patients with active infection and should be discontinued in the case of a serious infection. Mild upper respiratory tract or urinary tract infections are not a reason to stop anti-TNF agents. Patients with hepatitis B who were treated with a TNF inhibitor had worsening symptoms, viral load, or hepatic function, and although hepatitis B reactivation has been added to the label, concomitant antiviral treatment can be given.

Concern remains regarding the development of malignancy, particularly lymphoma. Patients must be observed closely for the occurrence of malignancies. However, any association is difficult to decipher because of the known increased incidence of malignancy in patients with rheumatoid arthritis. Aggressive and fatal hepatosplenic T-cell lymphomas, a rare malignancy, have been reported in patients receiving TNF blockers. Most cases occurred in patients getting infliximab for Crohn’s disease or ulcerative colitis who had received concomitant treatment with azathioprine or 6-mercaptopurine; the majority involved adolescent boys and young adult men.

In information obtained from manufacturers of TNF inhibitors approved for use in children (etanercept, infliximab, adalimumab), 48 cases of malignancies in children and adolescents were identified. It was estimated that 14,837 children received infliximab, 9200 received etanercept, and 2636 received adalimumab during the studied period. Approximately half of the malignancies were lymphomas. Others included leukemia, melanoma, and solid organ cancers. Eleven of the patients died (nine from hepatosplenic T-cell lymphoma, and one from T-cell lymphoma). The rates of malignancy were higher with infliximab than expected rates, but the primary use of infliximab was for inflammatory bowel disease in contrast to etanercept, where patients with JIA represented the majority. Eighty-eight percent of cases were in patients taking other immunosuppressive medications such as azathioprine, 6-mercaptopurine, or contradistinction MTX. It was concluded that there is an increased risk of malignancy with TNF-inhibitor exposure, but that the strength of the association, or a definite causal relationship could not be assigned. Some major problems with these conclusions were that the precise denominator for users was not known, and treated patients were not compared to a control group of JIA patients not treated with biologics. Bernatsky et al., using data from three Canadian centers, did not find an increased incidence of malignancy in patients with JIA. In contrast, Simard et al., using comprehensive administrative data from Sweden, showed that the incidence of malignancy in patients with JIA had increased in the years 1987 to 1999 (before the use of biologics) compared to the preceding two decades. Using national Medicaid data from 2000 through 2005, Beukelman et al. showed that children with JIA in the United States appeared to have an increased incidence of malignancy compared with children without JIA and that the treatment for JIA, including TNF inhibitors, did not appear to be significantly associated with the development of malignancy. Similar data were reported by Nordstrom et al. Thus the role of anti-TNF agents in increasing the risk of malignancy in patients with JIA is not yet clear. A meta-analysis in adults concluded that etanercept is safer than anakinra, adalimumab, or infliximab.

The safety of anti-TNF therapy during pregnancy is unknown, and it is classified as a category B medication, meaning that there is no evidence of risk in humans or if human studies have not been done, no evidence in animals that show risk. Many reports have documented lack of teratogenicity with healthy pregnancy outcomes. Similarly, breast-feeding appears to be safe. Consideration should be given to avoiding live viral vaccines for 6 months in children who have been exposed to biologic therapy during pregnancy.

Similar concerns exist for the development of demyelinating syndromes, especially multiple sclerosis, with anti-TNF therapy. Early postmarketing studies suggested that demyelinating syndromes, including multiple sclerosis, might be more common in patients treated with etanercept. In a trial of lenercept, another TNF antagonist, used to treat patients with multiple sclerosis, those taking the active drug had more exacerbations than those who did not. Patients with JIA have developed demyelinating syndromes, as have adults with RA. Guillain-Barré syndrome developed in 15 patients identified from the FDA database. In children, four cases of optic neuritis have been reported. On the other hand, large studies have failed to demonstrate an occurrence greater than what would have been expected. Patients with previous demyelinating syndromes should not be treated with TNF antagonists, and those with a strong family history should be observed carefully for the development of symptoms that may be suggestive of demyelination. Performing a baseline central nervous system MRI should be considered in patients with a family history of multiple sclerosis.

TNF antagonist therapy has been rarely associated with SLE-like syndromes and antiphospholipid antibody syndrome. The development of leukocytoclastic vasculitis had been reported in 35 patients; the disease resolved in the majority after discontinuation of anti-TNF therapy. New-onset psoriasis and Crohn disease have been reported.

In trials in patients with congestive heart failure (CHF), neither infliximab nor etanercept was effective, and the drugs may have even worsened the CHF. These agents might exacerbate, or even induce, CHF in patients with no previous risk factors. A meta-analysis in adults with plaque psoriasis found no effect of TNF inhibitors on cardiovascular events. A systematic review showed that TNF inhibition did not lead to significant changes in intima-media thickness, endothelial function, or lipid profiles over 52 weeks.

It does not seem that any specific laboratory monitoring is required routinely for any of these agents. Although the induction of antinuclear antibodies is common (up to approximately 15% of patients), screening for them is necessary only if suspicion of a developing autoimmune disease (e.g., drug-induced lupus) is raised.

As with most safety signals from postmarketing surveillance, it is difficult to know whether or not these cases are related to anti-TNF therapy, concomitant therapy, the underlying diseases, or demographics of the patients being treated, but caution is required when considering offering this therapy to candidate patients. It may not be entirely correct to lump all TNF inhibitors together as their mechanisms, pharmacokinetics, and hosts may differ, particularly with the nonmonoclonal antibody etanercept.

Guidelines developed for adults suggest withholding biologic DMARDs for at least 1 week before and after surgery. No specific recommendations regarding the use of biologic DMARDs during pregnancy or breast-feeding were made because of conflicting evidence.

IL-1 inhibitors

Anakinra.

IL-1 plays a prominent role in RA by stimulating synoviocytes and chondrocytes to produce small inflammatory mediators (e.g., prostaglandins) and matrix metalloproteases (MMPs) that lead to cartilage destruction and bone erosions. IL-1 also increases the expression of receptor-associated NF-κB ligand (RANK ligand), leading to osteoclast differentiation and activation and bone destruction. It exerts its effect by binding to the IL-1 receptor and through cell signaling and production of these various molecules and cytokines. IL-1 receptor antagonist (IL-1Ra), is a naturally occurring, acute phase antiinflammatory protein, part of the IL-1 supergene family. Anakinra is a manufactured IL-1Ra.

IL-1Ra is the most important physiologic regulator of IL-1–induced activity. By binding to the IL-1 receptor on cell surfaces, it prevents the interaction of the receptor with IL-1 and subsequent cell signaling. An imbalance between IL-1 and IL-1Ra can lead to uncontrolled inflammation.

Anakinra is a human recombinant form of IL-1Ra. It has a short half-life of 4 to 6 hours (when given at a dose of 1 to 2 mg/kg in adults with RA ) and requires daily subcutaneous injection. Dramatic responses to anakinra in some cases of systemic JIA and cryopyrin-associated periodic syndrome (CAPS), and the deficiency of the IL-1 receptor antagonist (DIRA) provide the evidence for pediatric use ( Table 13-12 ). These responses also provide evidence that this group of disorders are IL-1 driven and autoinflammatory in nature (see below).

TABLE 13-12

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