What are the potential side effects and usage considerations for Remicade (infliximab) in patients with autoimmune diseases, such as rheumatoid arthritis, Crohn's disease, or psoriasis, particularly those with a history of tuberculosis or hepatitis?

Remicade (Infliximab): Usage and Side Effects

Remicade is a highly effective TNF-alpha inhibitor approved for rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis, but carries significant risks including serious infections (particularly tuberculosis reactivation), infusion reactions, hepatotoxicity, and potential malignancy that require mandatory pre-treatment screening and ongoing monitoring. 1, 2

Approved Indications and Usage

Infliximab has regulatory approval for multiple autoimmune conditions 1:

• Refractory rheumatoid arthritis (must be combined with methotrexate) 3, 4
• Moderately to severely active Crohn's disease and fistulizing disease 1, 5, 6
• Ulcerative colitis 1
• Ankylosing spondylitis 1
• Psoriatic arthritis 1
• Plaque psoriasis 1

Treatment Sequencing Requirements

For rheumatoid arthritis, infliximab should only be initiated after documented inadequate response to methotrexate at therapeutic doses (≥15-25 mg/week for ≥3 months) and must be given in combination with methotrexate, not as monotherapy. 3, 4

Standard dosing is 3-5 mg/kg administered intravenously at weeks 0,2, and 6, followed by maintenance infusions every 8 weeks 1, 4, 5, 6. Dose escalation to 10 mg/kg or interval shortening to every 4 weeks may be considered only after establishing incomplete response to standard dosing 4.

Major Side Effects and Safety Concerns

Infections (Most Common Serious Adverse Event)

Infections are the most common adverse events with infliximab, with risk increased approximately twofold compared to baseline. 1

• Upper respiratory tract infections and urinary tract infections are most frequent but typically not serious 1
• Serious infections include pneumonia, bronchitis, sepsis, cellulitis, systemic fungal infections, and herpes zoster 1, 2
• Opportunistic infections are of particular concern, including atypical mycobacteria, histoplasmosis, coccidioidomycosis, Pneumocystis pneumonia, candidiasis, and aspergillosis 1

Tuberculosis Reactivation (Critical Risk)

Tuberculosis reactivation is a major concern with infliximab, with rates historically reported as high as 1893 cases per 100,000 patient-years before implementation of screening protocols. 1

• The risk of TB may be greater with infliximab (103 per 100,000 patient-years) compared to etanercept (39 per 100,000 patient-years) 1
• At least 50% of TB cases associated with infliximab are extrapulmonary, presenting atypically 1
• Median time from initiation to TB diagnosis is 3 months, suggesting reactivation of latent disease 1
• Even when latent TB is identified and treated prior to therapy, patients may still develop clinical infection, requiring high index of suspicion throughout treatment 1

Infusion Reactions

Infusion reactions occur in 3-22% of patients with psoriasis 1, 7:

• Most reactions are mild to moderate 7
• Acute infusion-related reactions include diverse symptoms and rarely anaphylactic shock 1
• Delayed hypersensitivity reactions can occur 1
• Antibodies to infliximab (ATI) can develop, increasing risk of immunological reactions and reducing efficacy 1, 8
• Serum sickness or combinations of arthralgia/myalgia with fever and/or rash occurred in 1% of psoriasis patients, with 6 requiring hospitalization 2

Hepatotoxicity

Hepatotoxicity manifests as transient, asymptomatic elevation in liver transaminases in most cases, but rare cases of severe hepatitis and acute liver failure resulting in transplantation or death have been reported. 1

• After 24 weeks of infliximab treatment, 6% and 2% of patients had markedly abnormal increases in ALT and AST respectively (defined as >150 U/L and 100% increase from baseline) 1
• The FDA issued a warning in 2004 regarding potential severe hepatic failure with infliximab 1
• Hepatitis B reactivation can occur with infliximab therapy 1

Malignancy Risk

The relationship between infliximab and malignancy remains uncertain, with insufficient data to definitively determine increased risk, particularly outside rheumatoid arthritis populations. 1

• Non-melanoma skin cancer (NMSC): increased risk reported with relative risk 1.7 (95% CI 1.3-2.2) 1
• Melanoma: relative risk 2.6 (95% CI 1.0-6.7) 1
• Hepatosplenic T-cell lymphomas reported in postmarketing studies, particularly in adolescent and young adult patients with Crohn's disease receiving concomitant azathioprine or 6-mercaptopurine 1
• In one COPD trial, 9 of 157 patients in the infliximab arm developed malignancy versus 1 of 77 with placebo (not statistically significant) 1
• In psoriasis studies, 7 of 1123 patients receiving infliximab developed at least one NMSC compared to 0 of 334 placebo patients 2

Cardiovascular Risks

Infliximab is contraindicated in patients with severe congestive heart failure (NYHA class III or IV), as trials showed increased mortality with high-dose infliximab (10 mg/kg) in this population. 1

• The ATTACH trial in severe heart failure was prematurely discontinued due to excess mortality 1
• Numerous postmarketing reports of worsening heart failure during therapy 1
• Median onset of new or worsening heart failure was 3 months after starting infliximab 1

Neurological Events

• CNS demyelination disorders have been reported sporadically, though they may occur with lesser frequency with infliximab compared to other TNF inhibitors 1
• Patients with personal history of demyelinating conditions should avoid infliximab 1

Autoimmune Phenomena

• Lupus-like syndromes with positive antibodies reported but rare 1
• Generally resolved within 6 weeks to 14 months of discontinuation 1
• Development of anti-nuclear antibodies is more common than clinical lupus 1

Hematologic Effects

Rare reports include leukopenia, neutropenia, thrombocytopenia, anemia, and hemolytic anemia 1, 2.

Mandatory Pre-Treatment Screening

Before initiating infliximab, the following screening is mandatory: 1, 3

• Tuberculosis screening: PPD or interferon-gamma release assay (IGRA) 1, 3
• Hepatitis B and C serology 1, 3
• Complete blood count (CBC) 3
• Liver function tests 3
• Assessment for active infections 1
• History of malignancy and cardiovascular disease 1

Contraindications to Therapy

Infliximab should not be started in the presence of active infection and should be discontinued if serious infection develops. 1

Additional contraindications include 1:

• Active viral hepatitis 1
• Severe CHF (NYHA class III or IV) 1
• Current or recent malignancy (unless diagnosed and treated >5 years previously or high likelihood of cure, including adequately treated NMSC) 1
• Personal history of demyelinating disorders 1

Ongoing Monitoring Requirements

Throughout treatment, patients require: 1, 3

• Periodic history and physical examination focusing on signs of infection 1, 3
• Temperature monitoring with immediate reporting of fever 1
• Consideration of yearly PPD testing 3
• Periodic CBC and liver function tests 3
• Monitoring for viral hepatitis reactivation in patients with history of viral hepatitis or chronic carrier states 1
• Regular comprehensive dermatological assessment for skin cancer, especially in high-risk patients 1

Response Assessment

Patients should be reviewed 2-4 weeks after completing loading doses to assess response and optimize maintenance dosing based on clinical response, serum drug and anti-drug antibody concentrations, inflammatory markers, faecal biomarkers, or endoscopy. 1

Special Populations and Precautions

Patients with History of Tuberculosis

• Careful screening at appropriate intervals required for patients at increased risk (institutional workers, frequent travelers abroad) 1
• High index of suspicion must be maintained throughout treatment even after prophylaxis 1

Patients with Hepatitis

• Use should be avoided if active viral hepatitis is present 1
• Hepatitis C: Exercise great caution; consultation with liver specialists recommended; interval monitoring of aminotransferases and viral load necessary 1
• Hepatitis B: Risk of reactivation; concurrent antiviral therapy may be needed 1

Patients with Prior Extensive Phototherapy

Infliximab is relatively contraindicated in patients who have had >200 PUVA and/or >350 UVB treatments, especially when followed by ciclosporin. 1

Pediatric Considerations

In pediatric Crohn's disease patients, certain adverse reactions occurred more frequently than in adults 2:

• Anemia (11%), leukopenia (9%), flushing (9%), viral infection (8%), neutropenia (7%), bone fracture (7%), bacterial infection (6%), respiratory tract allergic reaction (6%)
• Infections reported in 56% of pediatric patients versus 50% of adults 2

Drug Interactions and Precautions

• Live vaccines should be avoided while on infliximab therapy 1
• Concomitant use with azathioprine or 6-mercaptopurine increases risk of hepatosplenic T-cell lymphoma 1
• Methotrexate co-medication delays decline in infliximab serum concentrations and is required for rheumatoid arthritis 3, 4, 9

Patient Education Points

Patients must be instructed to 1:

• Check temperature frequently and report fever immediately
• Report signs of infection: cough, aches, fever, chills, wound redness/pain/discharge, burning with urination, nausea, vomiting, diarrhea
• Report shortness of breath or breathing changes
• Avoid raw or partially cooked dairy, fish, or meat products; unpasteurized milk; unwashed salads (Salmonella and Listeria risk) 1

Common Pitfalls to Avoid

• Do not initiate infliximab without documented inadequate response to conventional therapy (particularly methotrexate in rheumatoid arthritis) 3, 4
• Do not use infliximab as monotherapy for rheumatoid arthritis—must be combined with methotrexate 3, 4
• Do not overlook TB screening or dismiss atypical presentations of TB reactivation 1
• Do not continue therapy in presence of serious infection 1
• Do not use in severe heart failure 1
• Do not substitute biosimilars without physician supervision and patient agreement 1