Infliximab

Observational studies

A total of 33 patients with plaque psoriasis were treated with infliximab 5 or 10 mg/kg by intravenous infusion [ ]. One patient treated with infliximab 10 mg/kg complained of severe itching of the feet, which resolved on withdrawal. Three of 33 patients had infusion reactions, which were generally mild and transient. There were infections (for example cellulitis, tooth abscess, ear infection, infected wisdom tooth, bronchitis, pneumonia) in seven patients.

Seven patients with various inflammatory disorders were treated with infliximab 5 mg/kg by intravenous infusion; three had pityriasis rubra pilaris, one had panniculitis, one had eosinophilic fasciitis, one had discoid lupus erythematosus, and one had necrobiosis lipoidica diabeticorum [ ]. One patient with discoid lupus erythematosus did not respond to treatment and reported insomnia and mild confusion, which resolved after 1 month.

Five patients with hidradenitis suppurativa were treated with infliximab 5 mg/kg by intravenous infusion [ ]. All improved. One developed a tender submandibular swelling; a fine needle aspirate of the enlarged lymph node showed acid-fast bacteria, but culture was negative. This patient was treated for presumed Mycobacterium tuberculosis infection, with reduction of the size of the node. The number of patients in this series was small, but the authors commented that tuberculosis in infliximab-treated patients has previously been reported to be more common than expected.

When infliximab-related adverse drug reactions were studied in 32 patients with rheumatoid arthritis, there were 43 reactions in 21 patients, four patients had serious reactions, and in five patients infliximab was withdrawn [ ]. Adverse reactions consisted of infections (n = 21), allergies (n = 3) and cardiovascular complications (n = 3). The incidence of reactions was as follows: respiratory 28%; urinary 22%; cutaneous 16%; allergic 9.4%; cardiovascular 9.4%.

TNF-alfa has been suggested to be an important mediator of circulatory disturbances in alcoholic hepatitis. The effects of infliximab on portal and systemic hemodynamics have been studied in 10 patients with severe biopsy proven alcoholic hepatitis [ ]. After treatment, serum bilirubin, C-reactive protein, white cell count, and plasma concentrations of interleukin-6 and interleukin-8 were significantly reduced. Nine of 10 patients were alive at 28 days. Mean hepatic venous pressure gradient fell significantly at 24 hours. Mean arterial pressure and systemic vascular resistance increased significantly, mirrored by a reduction in cardiac index. Hepatic and renal blood flow also increased significantly. There was also a reduction in hepatic inflammation and improved organ blood flow, suggesting an important role for TNF-alfa in mediating circulatory disturbances in alcoholic hepatitis. The authors concluded that infliximab produces a highly significant, early, and sustained reduction in hepatic venous pressure gradient in patients with alcoholic hepatitis, possibly by a combination of reduced cardiac output and intrahepatic resistance.

In 23 patients with refractory autoimmune uveitis, who were given three infusions of infliximab at weeks 0, 2, and 6, 78% had clinical success, but only 50% continued infliximab therapy for at least 1 year [ ]. There was an unexpectedly high rate of adverse events. Seven patients had serious adverse events, including three cases of serious thrombosis, two vitreous hemorrhages, one malignancy, one new-onset congestive heart failure, and two possible cases of drug-induced lupus-like syndrome.

Data from 5000 patients with active rheumatoid arthritis treated with infliximab have been collected by Tanabe Seiyaku Co, Ltd [ ]. The overall risk of adverse reactions was 28% and of serious adverse reactions 6.2%, including bacterial pneumonia 2.2%, tuberculosis (n = 14), Pneumocystis jirovecii pneumonia (n = 22), interstitial pneumonitis (n = 25), and serious infusion reactions (n = 24); other adverse reactions included transient liver damage, gastroenteritis, and local skin infections. Most recovered after intensive treatment, but three patients (one with bacterial pneumonia and two with interstitial pneumonitis) died. There were 14 cases of tuberculosis in the early stages of treatment and half were extra-pulmonary. Serious infusion reactions included anaphylactic reactions (n = 8) and hypotension (n = 9); all recovered completely.

In a retrospective study of adverse events possibly related to infliximab in 500 consecutive patients with Crohn’s disease who had received a median of three infusions, the median duration of follow-up was 17 months [ ]. Serious adverse events were attributed to infliximab in 30 patients (6%). The most frequent adverse reactions were infections (41 patients, of whom 15 had a serious infection), acute infusion reactions (19 patients, of whom two had life-threatening reactions), serum sickness-like diseases (14 patients, of whom five had severe disease), lupus-like syndrome (three patients, including one with positive rechallenge after a subsequent infusion), malignant disorders (two solid tumors and one case of non-Hodgkin’s lymphoma), worsening of heart failure (one patient with a previously diagnosed cardiomyopathy), and demyelination syndrome (one patient). Among 10 deaths, five were considered to be possibly related to the treatment (four severe infections and one case of lung cancer).

Of 217 patients who received infliximab (mean number of infusions 2.6) for inflammatory bowel diseases, 41 had 42 severe adverse events [ ]. Most of these consisted of hypersensitivity reactions (n = 13), infections (n = 11), postoperative complications (n = 7), thromboembolic events (n = 5), or lymphomas (n = 3). There was also one case each of lupus-like syndrome, depression, and vestibular neuronitis. Six patients died, and the cause of death was lymphoma in two patients, infections in three, and pulmonary embolism in one. However, it was not stated how the causal relation to infliximab treatment was assessed. The authors noted that the annual incidence of lymphoma in their patients was 1.5%, which is considerably higher than the 0.015% expected from the background population data in their country. They also commented on the unexpectedly 2.8% mortality rate during the 2-year follow-up period.

In 100 patients treated with infliximab for inflammatory bowel disease there were adverse events in 10 patients after a median follow-up of 26 months [ ]. There were acute infusion reactions in two patients, a serum sickness-like reaction in one, bacterial or viral infections in four, pancytopenia in one, and surgical complications in two. There were no malignancies, autoimmune diseases, or neurological or cardiovascular adverse events.

In an analysis of the FDA’s AERS database infliximab was identified as the suspect medication in 18 220 reports [ ]. There were signals for lymphoma (EB05, the lower bound of the 90% confidence interval around the Empirical Bayes Geometric Mean = 6.9), neuropathy (EB05 = 3.8), infection (EB05 = 2.9), and bowel obstruction (EB05 = 2.8). The signal for granulomatous infections was stronger than the signal for non-granulomatous infections (EB05 = 13 and 2.4 respectively). The signals for bowel obstruction and infusion reaction were specific to patients with inflammatory bowel disease; this suggests potential confounding by indication, especially for bowel obstruction.

During post-marketing surveillance for 6 months of 5000 patients treated with infliximab for rheumatoid arthritis, 28% had adverse drug reactions, of which 6.2% were severe [ ]. Bacterial pneumonia occurred in 2.2%, tuberculosis in 0.3%, Pneumocystis jirovecii pneumonia in 0.4%, and interstitial pneumonitis in 0.5%. There were serious infusion reactions in 0.5%.

In 147 patients with inflammatory bowel disease who received 1924 infusions of infliximab, 21 were hospitalized because of serious infections that were considered to have been at least possibly related to infliximab [ ]. Nine patients (6%) developed malignancies during follow-up: four had colorectal carcinoma, one had a carcinoid tumour with another primary signet-ring cell carcinoma of the small bowel, one had a breast cancer, two had skin cancers, and one had a superficial melanoma.

Of 165 patients who were treated with infliximab 3 mg/kg every 8 weeks serious infections occurred in 8.5% [ ].

In 78 patients with juvenile idiopathic arthritis reactions during infusion, such as dyspnea, flushing, chills, headache, hypotension, anxiety, and throat edema, occurred in 29 (35%) [ ]. Anti-DNA antibodies were present in seven, but none developed a lupus-like syndrome.

Comparative studies

In a retrospective study, 122 patients with Crohn’s disease who received infliximab infusions were also given azathioprine (n = 47), mercaptopurine (n = 11), methotrexate (n = 23), prednisone (n = 64), mesalazine (n = 51), and antibiotics (n = 16) [ ]. Mean follow-up was 52 weeks (14–864 days). The overall response rate to infliximab was similar between patients who received immunomodulators and patients who received infliximab alone. There were more frequent adverse drug reactions in those who took infliximab alone (22%) than in those who took methotrexate (13%) and azathioprine/mercaptopurine (14%), but this was not statistically significant. Concomitant use of immunomodulators with infliximab in patients with Crohn’s disease did not improve clinical response rates, dosage reduction of prednisone, fistula response, and mean intervals between infliximab infusions.

Cardiovascular

The preliminary results of a phase II trial in patients with moderate to severe congestive heart failure showed a higher incidence of worsening congestive heart failure and death in patients treated with infliximab compared with placebo [ ]. This led to warnings from regulatory agencies and to the limited use of infliximab in patients with congestive heart failure.

Venous thrombosis has been associated with infliximab in two patients.

• A 55-year-old woman with psoriatic arthritis and possible systemic lupus erythematosus developed inspiratory pain, slight dyspnea, and left leg pain 1 week after receiving a second infusion of infliximab 3 mg/kg [ ]. A respiratory infection was suspected and she recovered. Similar pulmonary symptoms with right leg pain recurred 6 days after her third infusion of infliximab, and a pulmonary embolism was suggested on spiral CT. She also had raised anti-DNA antibodies and slightly raised cardiolipin antibodies.

• A 45-year-old woman with no history of hypertension, hypercholesterolemia, or diabetes received infliximab for Crohn’s disease [ ]. She had visual changes after her third dose of infliximab and ophthalmoscopy showed retinal vein thrombosis. There was no underlying coagulation disorder.

Although vascular complications have been associated with Crohn’s disease or rheumatoid arthritis, there was a close temporal relation with infliximab treatment in both cases. In addition, the second patient had no evidence of susceptibility factors.

There are reports that suggest that infliximab can precipitate thrombotic events in patients with various underlying diseases [ ].

It is not yet known whether infliximab has a negative procoagulant effect, but experimental data suggest that TNF-alpha has a strong antithrombotic activity in mice [ ]. In contrast, prolonged use of infliximab in seven patients with rheumatoid arthritis improved endothelial function assessed by brachial ultrasonography, at least during the first 7 days after infusion [ ].

A 78-year-old woman with rheumatoid arthritis and first-degree heart block was given infliximab 3 mg/kg fortnightly and after the third dose progressed to complete heart block [ ].

Respiratory

Allergic granulomatosis of the lung has been described after a second infusion of infliximab in one of 35 patients with active ankylosing spondylitis [ ]. The clinical and radiological symptoms resolved 8 weeks after withdrawal, but no other details were given.

• A 32-year-old man with Crohn’s disease developed an eosinophilic pleural effusion soon after a second infusion of infliximab [ ]. He recovered within 8 weeks, but the effusion recurred after infliximab re-treatment 1 year later.

Severe interstitial pneumonitis has been attributed to infliximab.

• A 22-year-old woman with colonic and perianal Crohn’s disease developed a cough within hours of her first dose of infliximab [ ]. It became worse after the second dose and 5 weeks after the first infusion she was hospitalized with progressive breathlessness. A high-resolution CT scan of the thorax showed extensive ground glass shadowing with right apical peribronchial consolidation. Pulmonary function tests showed a marked restrictive pattern. Bronchoscopy showed normal endobronchial appearances and bronchial washings were negative for Pneumocystis jirovecii , fungi, acid-fast bacilli, and viruses.

• A 66-year-old woman developed non-infectious interstitial pneumonitis after a second infusion of infliximab [ ].

Four patients developed severe features of methotrexate pneumonitis shortly after they received their third infusion of infliximab, raising the possibility that infliximab could potentiate the pulmonary toxicity of methotrexate [ , ]. Three patients with rheumatoid arthritis and asymptomatic fibrosing alveolitis had acute fatal exacerbations of their lung disease after having received two or three doses of infliximab [ ].

Pulmonary damage in patients without prior pulmonary disease has also been attributed to infliximab.

• Two men aged 21 and 71 years developed hypersensitivity pneumonitis after infliximab treatment for Crohn’s disease [ ]. The first developed pulmonary symptoms after a single dose of infliximab, whereas the second had previously tolerated infliximab well for 1 year. The latter had focal interstitial chronic inflammation on transbronchial biopsy. Infectious causes were carefully ruled out in both patients.

• An 84-year-old woman with rheumatoid arthritis who had taken leflunomide for 6 months developed severe interstitial pneumonitis 1 week after a second dose of infliximab [ ]. Infliximab was withdrawn and leflunomide was continued. The course of the disease was marked by rapidly progressive end-stage pulmonary fibrosis.

• A 35-year-old woman with severe Crohn’s disease that had not responded to hydrocortisone, mercaptopurine, and mesalazine was given infliximab [ ]. Within 48 hours after a second dose she developed fever, a dry cough, and dyspnea, with severe respiratory distress and acute anemia. There was diffuse bilateral alveolar hemorrhage on a chest CT scan and she subsequently developed staphylococcal superinfection. There was full pulmonary recovery 6 months later.

In all cases a causal relation with infliximab treatment was based on a suggestive temporal association and reasonable exclusion of other causes. Possible leflunomide-associated interstitial pneumonitis, possibly aggravated by infliximab, could not be ruled out in the second report.

Exacerbation of pre-existing obstructive sleep apnea syndrome concomitant with infliximab infusion has been reported in a 62-year-old woman with rheumatoid arthritis [ ].

Nervous system

Features of aseptic meningitis have been reported after multiple infliximab injections [ ].

• A 53-year-old man with severe rheumatoid arthritis and mixed type III cryoglobulinemia received his first four injections of infliximab uneventfully, but 4 hours after the fifth injection had severe muscle pain in the lower limbs, which required morphine and abated within 3 days. Similar symptoms were observed after the sixth injection. There were no signs of meningitis, the cerebrospinal fluid contained lymphocytes and increased concentrations of protein and IgG. Cultures were negative and MRI scans of the brain and the spine were normal. The CSF was normal 1 month later.

The authors speculated that the most likely explanation for these observations was linked to the lack of transfer of high-molecular weight soluble receptors and IgG across the blood–brain barrier, implying that control of brain tumor necrosis factor alfa cannot be obtained with monoclonal antibodies. They thought that neurological complications in diseases other than multiple sclerosis might be related to control of tumor necrosis factor alfa in the periphery, resulting in an enhanced contribution of brain-derived tumor necrosis factor alfa or other cytokines, such as interleukin-1.

Neurological events suggestive of demyelinating disorders in patients treated with tumor necrosis factor alfa antagonists and reported to the FDA’s Adverse Events Reporting System have been reviewed [ ]. These included 17 cases temporarily associated with etanercept and two with infliximab, but complete information was lacking in a number of cases. The various hypothetical mechanisms by which tumor necrosis factor alfa antagonists might produce demyelinating events have been discussed [ ]. Briefly, they cause an increase in peripheral T cell autoreactivity, and their inability to cross the blood–brain barrier may account for exacerbation of central demyelinating disorders.

• A 19-year-old woman taking azathioprine developed symptoms of multiple sclerosis 2 weeks after a second infusion of infliximab [ ]. An MRI scan confirmed a demyelinating process and there was clinical improvement without a further change in MRI examination.

• A 50-year-old woman developed visual loss and ocular pain in the left eye 3 weeks after her last infusion of infliximab [ ]. An MRI scan showed isolated retrobulbar optic neuritis. She recovered spontaneously after withdrawal of infliximab.

Whether these cases occurred by chance or reflected a true relation between infliximab and demyelinating disease is a matter of debate. As reviewed elsewhere, the actual number of reported cases does not appear to exceed the expected incidence in the untreated population [ ].

A debatable case of rapidly progressive Parkinson’s disease has been attributed to infliximab in a 72-year-old woman [ ]. Until more data are available, this report should be considered as anecdotal.

Several cases of peripheral nerve disorders have emerged.

• Two women aged 28 and 45 years had an acute, predominantly motor neuropathy after infliximab for Crohn’s disease and collagenous colitis [ ].

• Multifocal motor neuropathy occurred in a 34-year-old woman with rheumatoid arthritis [ ].

The hallmark in these patients was the appearance of neurological symptoms after the fourth dose of infliximab and an electromyographic pattern of conduction block. Antiganglioside antibodies were detected in one patient and returned to normal within 6 months after withdrawal of infliximab. A possible autoimmune mechanism was suggested.

Sensory neuropathy has also been reported in two women with rheumatoid arthritis aged 41 and 48 years [ ]. The peripheral neuropathy was attributed to necrotizing vasculitis in one patient who first developed symptoms after her sixth infusion of infliximab, and to rapid exacerbation of pre-existing mononeuritis multiplex 8 hours after a first infusion of infliximab in the second patient.

Various other neurological abnormalities have been attributed to infliximab.

• A patient with rheumatoid arthritis developed the Miller Fisher syndrome variant of the Guillain–Barré syndrome while receiving infliximab. He had ataxia and dysarthria, which fluctuated in relation to each subsequent infliximab infusion and after 6 months culminated in areflexic flaccid quadriplegia [ ].

• A 55-year-old man with a 27-year history of ankylosing spondylitis received infliximab and developed back pain and a paraparesis. Radiography showed rapid exacerbation of pre-existing spinal pseudoarthrosis at T11–12. Although the myelopathy could have developed over time and been unrelated to infliximab, the history and radiographic course suggested that suppression of inflammation by infliximab improved his activities of daily living, which paradoxically exacerbated pre-existing spinal pseudoarthrosis and hastened the onset of subsequent myelopathy [ ].

• A 47-year-old man with rheumatoid arthritis received monthly infusions of infliximab 300 mg for 2 years [ ]. A brain MRI scan showed gadolinium enhancement of the cisternal segment of the right oculomotor nerve. There were no white matter lesions and no dural enhancement. After withdrawal of infliximab, the diplopia and ptosis gradually resolved over 3 months. The transient and isolated nature of the palsy described suggested demyelination. There was no evidence of infection, inflammation, or migraine.

Sensory systems

Optic neuropathy has been described in patients with rheumatoid arthritis taking infliximab. In three patients aged 54–62 years, blurred vision or visual field loss in one or both eyes occurred after the third dose [ ].

• A 54-year-old man had blurred vision 34 days after a third dose of infliximab. Co-medication consisted of leflunomide, prednisone, naproxen, diazepam, fluoxetine, famotidine, metoprolol, and paracetamol or codeine. Fluorescein angiography showed capillary dilatation and vascular leakage in both optic nerve heads. He did not recover vision with glucocorticoid therapy.

• A 62-year-old woman had blurred vision 40 days after a third dose of infliximab. Co-medication consisted of atenolol, enalapril or hydrochlorothiazide, salicylic acid, terfenadine, and rofecoxib. Fluorescein angiography showed profuse vascular leakage. The left eye had a central scotoma and the optic nerve head was pale. A fourth dose of infliximab was given 7 weeks after the third dose, after which symptoms started in the right eye with a central scotoma. Methylprednisolone did not improve vision.

• A 54-year-old man developed loss of vision field 2 weeks after a third dose of infliximab. Co-medication consisted of prednisone, diclofenac, and omeprazole. Fluorescein angiography showed capillary dilatation and vascular leakage in the optic nerve heads.

All three patients had the toxic form of anterior optic neuropathy and MRI scanning ruled out demyelinating optic neuritis. Glucocorticoids, given to exclude external temporal arteritis, did not improve vision in any of the patients. Accumulation was speculated to be a factor in this adverse effect, because all three patients developed anterior optic neuropathy after the third dose of infliximab.

A 65-year-old woman was given intravenous infliximab 3 mg/kg for rheumatoid arthritis, in addition to prednisolone 2.5 mg/day, methotrexate 2.5 mg/week, folic acid, disodium etidronate, omeprazole, and thyroxine, and developed endophthalmitis [ ].

In one patient an additional infusion of infliximab produced similar symptoms in the previously unaffected eye; vision failed to improve despite infliximab withdrawal and steroid treatment.

• Retrobulbar optic neuritis was diagnosed after the ninth dose of infliximab in a 55-year-old woman [ ]. MRI scanning showed demyelination of the left optic nerve and the visual field defect improved after treatment with prednisone.

Psychiatric

A 30-year-old woman with evolving ileocolonic Crohn’s disease received five intravenous infusions of infliximab 5 mg/kg over 2 years [ ]. About 2 hours after each infusion, she had a panic attack for 2–48 hours. After the fourth infusion, she needed paroxetine and bromazepam.

Metabolism

Body composition was assessed in patients with Crohn’s disease before and after treatment with infliximab at 1 and 4 weeks [ ]. There were significant increases in body weight at 4 weeks and serum leptin concentrations at 1 and 4 weeks. The increase in serum leptin occurred at 1 week, when there were no significant changes in weight and fat mass, and was associated with down-regulation of TNF alfa-regulated mediators, soluble TNF receptor type II, and soluble intercellular antiadhesion molecule-1. Moreover, infliximab significantly increased cholesterol concentrations at 1 week compared with the control patients, who received methylprednisolone.

Infliximab was associated with very high concentrations of triglycerides in 32 patients with rheumatoid arthritis [ ].

Hematologic

A patient who had been treated for many years with classical therapy for rheumatoid arthritis developed a refractory anemia after treatment with infliximab + methotrexate [ ].

Pancytopenia has been reported on several occasions in patients taking infliximab.

• A 45-year-old woman with underlying renal insufficiency developed pancytopenia 2 weeks after a single infusion of infliximab for scleroderma [ ]. There were no other suspected drug exposures and she later died from infectious complications.

• Neutropenia and thrombocytopenia occurred in a 60-year-old woman [ ].

• Pancytopenia with bone marrow hypoplasia on biopsy occurred in a 66-year-old man [ ].

The second and third cases were complicated by the use of concomitant drugs (methotrexate, leflunomide) known to be associated with hematological disorders. Additional data are therefore required before adding hematological toxicity to the adverse effects of infliximab.

A hemophagocytic syndrome was reported a patient with rheumatoid arthritis treated with infliximab [ ].

• A 46-year-old woman with seropositive rheumatoid arthritis had active disease despite treatment with glucocorticoids, methotrexate, and sulfasalazine. Six weeks after the seventh infusion of infliximab 3 mg/kg she developed fever, dehydration, weight loss, profound lethargy, hepatomegaly, and pain in the right flank. She had thrombocytopenia (platelets 16 × 10 ⁹ /l), anemia, leukocytosis (15 × 10 ⁹ /l) lymphopenia (760 × 10 ⁶ /l), a low CD4 lymphocyte count (72 × 10 ⁶ /l), renal insufficiency, hyponatremia, hypoalbuminemia, and hypogammaglobulinemia. Liver enzymes were 20 times the upper end of the reference range, bilirubin 1.5 times, and lactate dehydrogenase five time. Urine and blood cultures grew Escherichia coli . Hemophagocytic syndrome was confirmed by bone marrow aspiration. Screening ruled out others possible causes than Escherichia coli and infliximab. Infliximab was withdrawn and the patient recovered with intravenous immunoglobulin and antibiotics.

The possible role of infliximab in the development of hypercoagulability disorders has been discussed in the context of a case of arterial thrombosis [ ].

• A 72-year-old woman with refractory sarcoidosis developed venous thrombosis at a catheter site and extensive multiple thromboses in small arteries in her legs after receiving a third dose of infliximab for severe enteropathy. Anticardiolipin antibodies were detected, but antinuclear and anti-double-stranded DNA antibodies were negative.

Although infliximab has been associated with autoantibody production, it is not known whether it contributed to hypercoagulability in this patient.

The FDA's Adverse Event Reporting System has received 8 reports of hepatosplenic T cell lymphoma in young patients receiving infliximab in combination with other immunosuppressants [ ].

• A 63-year-old woman with rheumatoid arthritis, who received methotrexate, prednisolone, and infliximab developed an EBV-associated lymphoproliferative disorder after 30 months; on withdrawal of infliximab the disorder resolved rapidly [ ].

Liver

Acute hepatitis with infliximab has been described [ ].

• A 44-year-old woman, who had used oral contraceptives for many years and had taken mesalazine, mercaptopurine, and prednisone for Crohn’s disease for 7 years, developed clinical and biological signs of acute mixed hepatitis 19 days after a single dose of infliximab 5 mg/kg. There were no symptoms suggestive of hypersensitivity and liver histology showed cholestasis without inflammation or eosinophilia. Other causes, such as a recent viral infection (hepatitis A, B, C, cytomegalovirus, Herpes simplex ) or gallstones, were ruled out. Among various autoantibodies, only antinuclear antibody titers were slightly raised. Complete normalization was observed 2 months later.

Although the patient took other potentially hepatotoxic drugs, the time-course suggested that infliximab was the cause.

• A 28-year-old man with refractory ulcerative colitis developed acute cholestatic liver damage after a single infusion of infliximab [ ]. The liver damage resolved spontaneously within 6 weeks.

Although a direct relation between infliximab and the acute liver damage could not be definitely established, this case suggests that infliximab can cause direct liver damage, the course of which is similar to acute cholestatic hepatitis and resolves after withdrawal of the drug.

Skin

Skin reactions, including erythema multiforme in three patients and a lichenoid eruption in one, were attributed to infliximab [ ]. One patient had similar lesions after etanercept. Patch tests with infliximab in three patients were negative, but produced a flare-up of lesions in one patient and recurrence of malaise and nausea in another patient, suggesting that infliximab is well absorbed percutaneously.

There is a multitude of reports of the adverse effects of infliximab on the skin, including palmoplantar pustulosis [ ], alopecia areata [ ], halo nevi [ ], cutaneous mucormycosis [ ], suberythrodermic psoriasis [ ], dermatitis herpetiformis [ ], pustular psoriasis [ , ], atopic dermatitis [ ], acne [ , ], an overlap of exanthematous pustulosis and toxic epidermal necrolysis [ ], and an oral lichenoid reaction [ ].

Other skin reactions have been described in patients treated with infliximab, including lichenoid dermatitis, a perniosis-like eruption, and superficial granuloma annulare, but coincidental eruptions could not be ruled out and the authors provided no convincing evidence of causal relations [ ]. Other cases with recurrence or flare of the skin lesions on rechallenge gave more definitive evidence of the role of infliximab and included eczematous purpura of Doucas and Kapetenakis [ ], eczema-like toxiderma [ ] and an atopic dermatitis-like eruption [ ].

• A 36-year-old man developed a diffuse pruritic rash after treatment for 3 months with oral leflunomide and infliximab for palmoplantar pustular psoriasis [ ]. Withdrawal of both drugs resulted in improvement in the skin condition. Although patch tests to both leflunomide and infliximab were negative, rechallenge with infliximab resulted in recurrence of the eczematous rash.

• Alopecia areata occurred in a 51-year-old woman with rheumatoid arthritis and Sjögren’s syndrome who received infliximab for 11 months [ ]. She developed non-scarring hair loss consistent with alopecia areata, which eventually evolved to 100% scalp involvement despite withdrawal of infliximab.

• A 23-year-old man with a history of Crohn’s disease developed profuse warts on his penis and perianal region after two doses of infliximab [ ]. A diagnosis of genital condylomata acuminata was made.

• A 72-year-old man developed bullous skin lesions the day after receiving his fourth dose of infliximab for rheumatoid arthritis [ ]. Human antichimeric antibodies were positive, as were antinuclear antibodies, and he completely recovered after treatment with prednisone.

Four patients with no previous history of psoriasis had psoriasis or psoriasiform cutaneous eruptions [ ] ( Table 1 ). As infliximab can improve severe psoriatic arthritis, a paradoxical adverse reaction to this agent was suggested.

Delayed onset of a short-lived maculopapular, urticarial rash has been reported in two children aged 10 and 16 years given infliximab for juvenile rheumatoid arthritis [ ]. They developed cutaneous lesions 13–18 days after the first or second injection, and later tolerated further infliximab administration well. There was no evidence of vasculitis on skin biopsy.

Two patients aged 20 and 56 years treated with infliximab for Behçet’s disease developed multiple lesions of erythema nodosum 3 and 30 days after their third and fourth infusions respectively [ ]. Infliximab-induced exacerbation of previous erythema nodosum was suggested in the first patient. Because new lesions of erythema nodosum subsequently developed despite withdrawal of infliximab in this patient, and because no documentation of the outcome was provided in the other patient, any causal relation should be considered doubtful.

A typical nicotinic acid-like reaction, consisting of intense chest tightness and erythematous flushing, occurred within minutes of a first or subsequent infusion of infliximab in three children with refractory juvenile rheumatoid arthritis [ ]. Similar reactions were observed after further infusions despite various prophylactic drug regimens, and only aspirin finally prevented recurrence.

Alopecia areata involving the scalp, eyebrows, and eyelashes has been reported in a 51-year-old woman who had received infliximab for 11 months for rheumatoid arthritis and Sjögren’s syndrome [ ].

Five patients developed erythematous annular plaques on the trunk and limbs while receiving four different TNF-α antagonists [ ]. One was taking lenalidomide for multiple myeloma, two were receiving infliximab, one was receiving etanercept for severe rheumatoid arthritis; and one was in a trial of adalimumab for psoriatic arthropathy. Skin biopsies showed diffuse interstitial granulomatous infiltration with lymphocytes, histiocytes, and eosinophils, and palisading degenerated collagen. Withdrawal of the medications led to complete resolution of the skin lesions.

Acute alopecia areata has been reported during treatment with infliximab in a subject who had never had it (cf. adalimumab and efalizumab) [ ].

In three patients with severe Crohn’s disease who required digestive surgery, infliximab before or immediately after surgery was discussed as an additional possible cause of postoperative poor wound healing with serious complications [ ].