Rash Induced by Anti-tumor Necrosis Factor Agents in an Teen with Crohn's Disease

Abstract

Background. A 17-year-old white male with Crohn's disease who was receiving maintenance infusions of the anti-tumor necrosis factor (TNF) agent, infliximab, presented with a new-onset psoriasiform skin rash. The rash was not responsive to topical or oral corticosteroids and worsened after infliximab infusions and after subsequent administration of a second anti-TNF drug, adalimumab.
Investigations. Full medical history and physical examination, including assessment of the morphology of rash and the temporal correlation with administration of anti-TNF agents.
Diagnosis. Anti-TNF-agent induced psoriasiform skin rash.
Management. Discontinuation of anti-TNF therapy. The patient opted to have his gastrointestinal symptoms treated with oral mesalazine and metronidazole.

A 17-year-old white male with a 9-year history of ileocolonic Crohn's disease developed a skin rash while receiving infliximab, a chimeric IgG1κ monoclonal antibody against tumor necrosis factor (TNF). For the first 5 years after his diagnosis he was treated with mesalazine, 6-mercaptopurine and intermittent corticosteroids. At 13 years of age, he developed corticosteroid-dependent gastrointestinal symptoms and 6-mercaptopurine-induced leukopenia, which required drug discontinuation, and began treatment with infliximab. His gastrointestinal symptoms responded well to the initial 3-dose induction course of infliximab 5 mg/kg per dose given by infusion at 0, 2 and 6 weeks and he was started on a maintenance course of infliximab 5 mg/kg per dose administered every 8 weeks. His infusion frequency was subsequently increased to every 6 weeks due to recurrence of gastrointestinal symptoms.

Within 2 weeks of his 34th infliximab infusion, the patient presented with oval plaques 1–3 cm long on his skin. The rash had started as a single, pruritic patch on his shoulder a few days before. As more lesions developed they were noted to be annular and scaly with a red, trailing border. He had some lesions on his neck but they were most dense on his flanks, abdomen, back and the extensor surfaces of his arms and legs (Figure 1). The palms of his hands and soles of his feet were spared. The patient was otherwise systemically well, without exacerbation of his gastrointestinal symptoms or evidence of active viral, bacterial or fungal infection. He did not have a previous history of psoriasiform skin rash and there was no family history of psoriasis or other diagnoses of dermatological conditions.


(Enlarge Image) Figure 1.
Diffuse, erythematous, annular patches with areas of confluence can be seen extending across the trunk in this 17-year-old adolescent, following treatment with infliximab. The eruption worsened following a subsequent infusion and improved on discontinuation of the drug.

The patient was referred to a pediatric dermatologist and a topical corticosteroid, triamcinolone acetonide ointment 0.1%, was prescribed and this led to a partial resolution of the rash. The eruption worsened again following the next infliximab infusion. He was then prescribed a 5-day course of oral prednisolone with a decrease in pruritis and severity of the rash, but the lesions recurred on discontinuation of this corticosteroid. Approximately 4 months after he first presented with the rash, infliximab therapy was discontinued and the patient was treated symptomatically with antihistamines and another course of prednisolone. It was recommended to the patient that a skin biopsy sample should be taken to establish the histopathology of the rash, but he and his parents refused this procedure. On follow-up examination approximately 5 weeks after his last dose of infliximab most of the lesions on the trunk of the patient had resolved, but some lesions remained on his knees, thighs and lower legs. Given the need to keep his gastrointestinal symptoms under control, he was given adalimumab, a recombinant human IgG1 monoclonal TNF antagonist, starting with an induction course of 160 mg administered subcutaneously followed by 80 mg 2 weeks later, with the plan to then give a maintenance dose of 40 mg every other week. However, after the second induction dose of adalimumab he had a marked exacerbation of the same rash and adalimumab was discontinued after the first maintenance dose at the patient's request. Spontaneous resolution of the lesions occurred over the next month. This confirmed the diagnosis of an anti-TNF-agent-induced psoriasiform skin rash. The skin manifestations caused the patient sufficient distress to prevent further use of a TNF antagonist. He was offered treatment with methotrexate as an alternate immunomodulator. However, he refused this medication and opted to have his symptoms of abdominal pain and diarrhea treated with intermittent combinations of up to oral mesalazine 4.8 g and metronidazole. After 3 years of follow-up, he has not had a recurrence of the rash. The patient continues to have some GI symptoms.

Figure 1.
Diffuse, erythematous, annular patches with areas of confluence can be seen extending across the trunk in this 17-year-old adolescent, following treatment with infliximab. The eruption worsened following a subsequent infusion and improved on discontinuation of the drug.

Discussion of Diagnosis

Anti-TNF agents are now widely used to induce and maintain remission in children and adults with Crohn's disease or ulcerative colitis.[1–6] This class of drugs has also been shown to be efficacious for other immune-mediated disorders including rheumatoid arthritis, psoriasis, systemic lupus erythematosis, spondylarthritis and lymphoproliferative diseases.[7] As the use of anti-TNF therapies has increased, reports have described a variety of cutaneous complications including hypersensitivity rashes, serum sickness-like and eczematous reactions, lichenoid eruptions, lupus-discoid-type rashes and psoriasiform rashes.[8–11] Of these, psoriasis and psoriasiform rashes have received the most attention given the paradoxical nature of this adverse event occurring with a class of drugs that is used to treat psoriasis.[12–18] In August 2009, the FDA issued an alert requiring the manufacturers of anti-TNF agents to update the prescribing information to make health-care professionals aware of the reported cases of 'new-onset psoriasis' in patients receiving these drugs.[19]

A literature search performed in 2009 showed reports of more than 100 adults developing psoriasis or a psoriasiform rash following anti-TNF therapy, with more than 60 developing new-onset lesions rather than reactivation of previous rashes.[11,20] Most of the patients described had rheumatoid arthritis as their underlying disease, while about 15 had been diagnosed with IBD.

Psoriasis is a chronic skin disease characterized by the presence of a hyperproliferative epidermis. There are various clinical phenotypes, but approximately 85–90% of all patients are affected by the most common variant, which is known as plaque psoriasis (or psoriasis vulgaris).[21] Guttate and pustular psoriasis is seen much less frequently.[22] The rash commonly seen with plaque psoriasis appears as raised, well-demarcated, erythematous oval plaques of variable sizes and shapes with adherent silvery scales. Although our patient's rash similarly consisted of well-demarcated oval plaques, the edges of the plaques were not as raised nor the scales as prominent as seen with plaque psoriasis. The incidence of psoriasis is greater among first-degree and second-degree relatives of patients than in the general population. In Crohn's disease, the risk of psoriasis is higher than in the general population.[23]

The prevalence of adult patients receiving TNF antagonists who develop psoriasiform rashes has been estimated to be 0.6–5.3%, with onset occurring a few days to up to 4 years after initiation of treatment.[22] Our case developed his rash 4 years after initiation of treatment with TNF antagonists. In our pediatric population with IBD, we estimate a prevalence of psoriasiform rashes of 3.1% among those receiving anti-TNF therapy, as we have noted that three other children have developed similar rashes to the case reported here, and the rashes in these children have also resolved after discontinuation of anti-TNF drugs. Interestingly, in patients with anti-TNF-induced psoriasis a 40% prevalence of palmoplantar pustular psoriasis has been described, which is much higher than the prevalence of <5% reported in the general psoriatic patient population.[22] A negative personal and family history of psoriasis has been noted in 75% of cases, which is similar to our case.[24]

Investigators have suggested that the etiology of psoriasis involves a dysregulation of the immune system, with important roles for interferon α (IFN-α) and proinflammatory cytokines such as TNF.[21] The mechanisms by which anti-TNF therapies can paradoxically induce new-onset psoriasiform rashes have yet to be clearly explained. One group of investigators postulated a role for an opportunistic infection when they reported that three cases of an anti-TNF-induced rash had Chlamydia trachomatis DNA in their skin biopsy samples.[25] However, evidence of infection has not been found in most of the reported cases, and it was not found in our patient either.[11]

The occurrence of psoriasis after treatment with TNF antagonists may be due to an imbalance in patients between TNF and IFN-α, as blocking TNF may lead to uncontrolled production of IFN-α.[26–28] One study compared biopsy specimens from 13 patients who had psoriasiform eruptions and were receiving anti-TNF agents with biopsy specimens from patients who had psoriasis but had not received these medications.[29] MxA, a protein whose expression is induced by IFN-α, was strongly expressed by inflammatory cells in the biopsy samples taken from patients with the drug-induced psoriasiform reactions and the expression of MxA was higher in those samples than in the control samples. Other researchers have noted that patients who had pustular psoriasis and had paradoxical worsening of their rash when treated with infliximab and with another anti-TNF agent, etanercept, had decreased TNF expression in their palmar eccrine glands and ducts compared with controls. They hypothesized that individuals with pustular psoriasis may have an already existing disturbance of TNF expression in their sweat ducts, which is made worse by anti-TNF therapy.[30] It is unknown whether a similar disturbance may explain the preponderance of palmoplantar psoriasis in the reported cases of anti-TNF-agent-induced rash. Unfortunately, because our patient and his parents refused a skin biopsy specimen to be taken, we could not assess the expression of TNF or IFN in his rash. However, we would recommend that patients with new-onset skin lesions be considered for referral to a dermatologist to help diagnose the eruption and assess the need for a biopsy procedure.

Treatment and Management

For the cases described in the literature, patients who have been diagnosed with anti-TNF-agent-induced psoriasiform rash have been treated with a variety of drugs that have had mixed results. Topical corticosteroids have been used in more than 50% of cases, but when used alone this treatment has led to resolution of the rashes in only about a quarter of cases.[22] Changing to a different TNF antagonist has not led to resolution of the rashes in 85% of the cases reported, suggesting a drug class effect. Discontinuation of anti-TNF therapy resolved the psoriasiform rashes in approximately 50% of patients, regardless of the underlying disorders. However, in the population of patients with IBD, in particular, this strategy has been more successful. A review of 18 patients with IBD (17 treated with infliximab and 1 with adalimumab) published in 2009 reported regression of lesions in 16 patients following withdrawal of infliximab.[20] In six of these patients infliximab was reintroduced with no further recurrence of the psoriasiform rash.[20] In our patient's case we reintroduced infliximab after trying topical and oral corticosteroids, but this did not prove successful as his rash recurred. We then used a second anti-TNF agent, adalimumab, but his rash also recurred after administration of this drug. Ultimately, our patient was sufficiently distressed with the symptoms of his rash that he opted to discontinue anti-TNF therapy.

For the gastroenterologist faced with a patient with IBD who has developed a new-onset rash after initiation of anti-TNF therapy, we recommend adopting an approach that takes into consideration whether or not the therapy can be discontinued in that particular individual (Figure 2). The patient should be questioned as to whether they have a previous history of cutaneous eruptions and to discern whether there is a family history of psoriasis or other dermatological conditions. Most patients with anti-TNF-induced rashes will give negative responses to these questions. As the response of the rash to therapy is related to the dosing schedule of the anti-TNF agent, it may be necessary to observe the patient following administration of more than one dose. A drug-induced rash would be expected to worsen with exposure to the drug, rather than improve.

On the basis of the successful reports of rash resolution in patients with IBD, such as our case, we recommend that discontinuation of the TNF antagonist should be considered, especially if there are other suitable options available, such as mesalazine, antibiotics, 6-mercaptopurine/azathioprine, methotrexate, surgery, or other biologic agents to treat the patient's IBD. For our patient, we believed that he could benefit from methotrexate treatment, but he preferred to have his symptoms treated with mezalazine and antibiotics rather than with further immunosuppressive therapies. Although he responded to these therapies he did not maintain clinical remission of his Crohn's disease for prolonged periods as he had with infliximab therapy. His rash resolved on cessation of anti-TNF therapy and after 3 years of follow-up it had not recurred. In cases in which it has been deemed that the management of the patient's IBD is dependent on anti-TNF therapy, or in which the rash did not resolve after drug discontinuation, aggressive topical and systemic therapy for treatment of psoriasis has been shown to ameliorate symptoms. Therapeutic options to treat the psoriasiform rash include the use of topical corticosteroids and keratolytic agents, or ultraviolet phototherapy, or the initiation of systemic therapy such as corticosteroids, ciclosporin or other non-TNF biologic agents.[21,24]

Conclusions

To our knowledge, our case is only the third pediatric patient with IBD and this cutaneous complication to be described in the literature, and the only one to be described as having developed a new-onset psoriasiform rash after treatment with two different TNF antagonists.[30,31]

The case highlights that this cutaneous complication is the result of a drug class effect and that it can occur in children, as well as adults, with IBD. The development of psoriasiform skin rashes with drugs proven to be efficacious for the treatment of psoriasis has caused confusion among clinicians and has, at times, led to inappropriate management of the rashes. Unfortunately, the current literature on this topic is replete with confusing terms such as "psoriasiform rash," "paradoxical psoriasis" and "psoriatic-like lesions". Given that these rashes are typically diagnosed based on clinical features without histological information, we suggest the use of the general term 'anti-TNF-induced psoriasiform rashes' until the etiopathogenesis has been more clearly defined. Further research is needed to understand the underlying mechanisms leading to development of these rashes and the risk characteristics of the affected patients. Development of evidence-based therapeutic interventions is also required to treat the anti-TNF-induced psoriasiform rashes effectively and enable the continued use of this class of agents.

Figure 2.

Suggested algorithm for the evaluation and treatment of patients with IBD who develop anti-TNF-induced psoriasiform rashes.