What are the risks of long-term biologics (biologic medications), systemic corticosteroids, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), and Disease-Modifying Antirheumatic Drugs (DMARDs)?

Long-Term Risks of Biologics, Systemic Corticosteroids, NSAIDs, and DMARDs

Long-term systemic corticosteroids pose the most serious risks to morbidity and quality of life, particularly affecting bone health and growth in children, and should be avoided whenever possible in favor of steroid-sparing treatments. 1

Systemic Corticosteroids: Highest Risk Profile

Long-term glucocorticoid therapy carries substantial risks that often outweigh benefits, even at low doses. 1

Major Adverse Effects

• Bone health deterioration and growth suppression in children, making long-term use inappropriate in pediatric populations 1
• Increased cardiovascular risk, particularly concerning given the high prevalence of cardiovascular comorbidities in inflammatory arthritis populations 1
• Infection risk elevation when used chronically or at doses ≥7.5 mg/day 2
• Metabolic complications including weight gain, diabetes, and hypertension 1

Clinical Management Strategy

• Taper and discontinue glucocorticoids first before attempting to reduce DMARDs or biologics once inactive disease is achieved 1
• Limit duration to shortest possible, using the lowest effective dose 1
• Strongly avoid as initial monotherapy in systemic conditions 1
• Use only as bridging therapy (courses <3 months) when absolutely necessary 3

Biologics: Moderate Risk with Specific Concerns

Biologics demonstrate a reasonable safety profile overall, with serious infections being the primary concern, though the risk varies by drug class. 1

Serious Infections

• Moderately increased risk compared to conventional DMARDs (adjusted incidence rate ratio 3.1-3.9 in some studies) 1
• Tuberculosis risk elevated with TNF inhibitors, especially monoclonal antibodies, requiring screening for latent TB before initiation 1, 4
• Opportunistic infections including atypical fungi and bacterial pathogens 4
• No significant difference in serious infection risk across different biologic classes 1

Herpes Zoster

• JAK inhibitors carry highest risk: 3-4 per 100 patient-years in Western populations, up to 9 per 100 patient-years in Japan/Korea 2
• TNF inhibitors show elevated rates compared to conventional DMARDs (2-3 per 100 patient-years) 2
• Other biologics (IL-6, IL-17, IL-12/23 inhibitors) do not show increased risk 1
• Recombinant zoster vaccine reduces risk by 81% and should be administered before biologic initiation 2

Malignancy Risk

• No increased risk of solid tumors with TNF inhibitors based on registry data 1, 4
• Non-melanoma skin cancers are more common with TNF inhibitors 1, 4
• Overall cancer risk not increased for biologics or targeted synthetic DMARDs 1
• Melanoma, cervical cancer, and hematological cancers show no consistent increased risk 1

Drug-Specific Risks

• IL-6 inhibitors (tocilizumab): Lower intestinal perforations (adjusted HR 4.5 vs conventional DMARDs, 2.6-4.0 vs TNF inhibitors) 1
• Rituximab: Progressive multifocal leukoencephalopathy (rare but serious) 4
• Abatacept: Pulmonary infections 4
• JAK inhibitors: Venous thromboembolism/pulmonary embolism (adjusted HR 1.3 vs TNF inhibitors) 1

Cardiovascular Events

• No increased risk of major adverse cardiovascular events (MACE) with biologics or targeted synthetic DMARDs 1

Long-Term Safety Profile

• Sustained efficacy without increased adverse events over extended treatment periods 5
• Low rates of serious adverse events requiring cessation with long-term use 5
• Antidrug antibody development remains low in long-term studies 5

NSAIDs: Cardiovascular and Gastrointestinal Risks

NSAIDs provide only symptomatic relief without disease modification and carry significant cardiovascular and gastrointestinal risks, particularly problematic in populations with frequent comorbidities. 1

Major Concerns

• Cardiovascular complications including increased risk of myocardial infarction and stroke, especially in patients with pre-existing cardiovascular disease 1
• Gastrointestinal toxicity including ulceration, bleeding, and perforation 1
• Renal impairment with chronic use 1
• No efficacy for skin psoriasis in psoriatic arthritis 1

Clinical Use Limitations

• Should not be used as monotherapy beyond 4 weeks for peripheral arthritis if disease activity persists 1
• May be extended to 12 weeks for predominant axial or entheseal involvement if providing relief by 4 weeks 1
• Benefit-to-risk ratio must be carefully considered, especially given frequent cardiovascular comorbidities in inflammatory arthritis populations 1

Conventional Synthetic DMARDs: Organ-Specific Toxicities

Conventional DMARDs have well-established safety profiles with organ-specific monitoring requirements, generally safer than long-term corticosteroids but requiring vigilance. 4, 6

Methotrexate

• Hepatotoxicity risk requiring regular liver function monitoring 4
• Cytopenia (bone marrow suppression) 4
• Pneumonitis, particularly during first year of treatment 4
• Teratogenicity requiring contraception in women of childbearing age 4

Leflunomide

• Hepatotoxicity similar to methotrexate 6
• Hypertension requiring blood pressure monitoring 6
• Peripheral neuropathy (rare) 6

Hydroxychloroquine

• Retinal toxicity requiring ophthalmologic screening, though rare with appropriate dosing 6
• Generally favorable safety profile compared to other DMARDs 6

Sulfasalazine

• Gastrointestinal intolerance (nausea, abdominal pain) 6
• Cytopenia requiring blood count monitoring 6
• Hypersensitivity reactions 6

Overall DMARD Safety

• Long-term use is generally safe when appropriate monitoring is performed 6
• Risks are manageable with regular laboratory surveillance 6
• Safety profile is reasonable compared to risks of uncontrolled disease 4

Critical Clinical Pitfalls to Avoid

Combination Therapy Risks

• Never combine TNF blockers with anakinra or abatacept due to increased serious infection risk without added benefit 7
• Avoid combining multiple biologics due to insufficient safety data and potential pharmacological interactions 7
• Higher serious infection rates observed with rituximab followed by TNF blocker 7

Vaccination Considerations

• Avoid live vaccines with all biologics and JAK inhibitors 7
• Administer pneumococcal and influenza vaccines before biologic initiation when possible 4
• Give recombinant zoster vaccine before starting biologics, especially JAK inhibitors 2

Infection Screening

• Screen for latent tuberculosis before all TNF inhibitor initiation 1, 4
• Rule out active infection before escalating immunosuppressive therapy 3
• Monitor for infections continuously during treatment 1

Drug Interactions

• Monitor CYP450 substrates (warfarin, cyclosporine, theophylline) when initiating or discontinuing biologics 7
• Methotrexate does not require dose adjustment when combined with adalimumab despite reduced clearance 7