12.4 DMARDs, Biologics, Antineoplastics & Immunosuppressants
Key Takeaways
Methotrexate inhibits dihydrofolate reductase and is dosed once weekly; daily dosing errors have been fatal, and folic acid reduces mucositis, cytopenias and liver toxicity.
Latent tuberculosis must be excluded before TNF inhibitors, which raise infection risk; JAK inhibitors carry boxed warnings for serious infection, malignancy, major cardiovascular events and thrombosis.
The 2022 ACR/AAHKS perioperative guideline for elective joint replacement continues conventional DMARDs, withholds biologics so surgery falls at the end of the dosing cycle, and withholds JAK inhibitors for 3 days.
Calcineurin inhibitors (cyclosporine, tacrolimus) cause nephrotoxicity, hypertension and tremor and are CYP3A4 substrates; mTOR inhibitors impair wound healing.
Capecitabine and 5-fluorouracil cause hand-foot syndrome, EGFR inhibitors cause paronychia and periungual granulation tissue, and taxanes, vinca alkaloids and platinum agents cause peripheral neuropathy.
12.4 DMARDs, Biologics, Antineoplastics & Immunosuppressants
The pharmacology outline lists anti-inflammatories (DMARDs and biologics) and chemotherapeutic agents (antineoplastics, antirheumatics and immunosuppressants). Rheumatoid arthritis, psoriatic arthritis, organ transplantation and cancer are common in podiatric patients. These drugs affect infection risk, wound healing, surgical timing and the skin and nails of the foot.
Conventional Synthetic DMARDs
| Drug | Mechanism | Monitoring and adverse effects |
|---|---|---|
| Methotrexate | Inhibits dihydrofolate reductase; at low weekly doses it also increases anti-inflammatory adenosine | Given once weekly; daily dosing errors have caused deaths. Folic acid supplementation; liver toxicity, cytopenias, pneumonitis, mucositis, teratogenic. TMP-SMX adds antifolate toxicity, and high-dose NSAIDs or PPIs can reduce methotrexate clearance |
| Hydroxychloroquine | Raises endosomal pH and interferes with antigen processing and Toll-like receptor signaling | Retinal toxicity: baseline and periodic eye examinations; QT effects |
| Sulfasalazine | Metabolized to 5-aminosalicylate and sulfapyridine | GI upset, reversible oligospermia, hemolysis in G6PD deficiency, sulfa hypersensitivity |
| Leflunomide | Inhibits dihydroorotate dehydrogenase (pyrimidine synthesis) | Hepatotoxicity, teratogenic with a very long half-life (cholestyramine washout) |
Biologic and Targeted Synthetic DMARDs
| Target | Drugs | Key cautions |
|---|---|---|
| TNF-alpha | Infliximab (chimeric), adalimumab, etanercept (soluble receptor), certolizumab, golimumab | Screen for latent TB and hepatitis B; serious infections; can worsen heart failure and demyelinating disease |
| IL-6 receptor | Tocilizumab, sarilumab | Suppresses CRP, so infection can be missed; GI perforation; lipid elevation |
| T-cell costimulation | Abatacept (CTLA-4-Ig blocks CD80/86) | Infections |
| CD20 (B cells) | Rituximab | Hepatitis B reactivation, PML, infusion reactions |
| IL-1 | Anakinra, canakinumab | Sometimes used for refractory gout flares |
| IL-17 and IL-12/23 or IL-23 | Secukinumab, ixekizumab; ustekinumab, guselkumab | Psoriasis and psoriatic arthritis; IL-17 inhibitors can worsen inflammatory bowel disease and raise Candida risk |
| JAK kinases (targeted synthetic) | Tofacitinib, baricitinib, upadacitinib | Boxed warnings: serious infections (including herpes zoster), mortality, malignancy, major adverse cardiovascular events and thrombosis |
Perioperative Management
The 2022 ACR/AAHKS guideline for elective hip and knee replacement in patients with rheumatic disease advises:
- Continue conventional DMARDs (methotrexate, leflunomide, hydroxychloroquine, sulfasalazine)
- Withhold biologics and time surgery for the end of the dosing interval
- Withhold JAK inhibitors for 3 days before surgery
- Restart once the wound is healing and no infection is present (often about 14 days)
Surgeons commonly apply these principles to elective foot and ankle surgery, coordinating with the patient's rheumatologist. Chronic corticosteroids are continued at the usual daily dose rather than stopped or given as routine stress doses.
Transplant and Other Immunosuppressants
| Class | Drugs | Mechanism | Key adverse effects |
|---|---|---|---|
| Calcineurin inhibitors | Cyclosporine (binds cyclophilin), tacrolimus (binds FKBP12) | Block calcineurin, so NFAT cannot drive IL-2 transcription | Nephrotoxicity, hypertension, hyperkalemia, tremor; tacrolimus causes post-transplant diabetes; cyclosporine causes gingival hyperplasia and hirsutism. CYP3A4 substrates: azoles and macrolides raise levels, rifampin lowers them |
| mTOR inhibitors | Sirolimus, everolimus | FKBP12 complex inhibits mTOR, blocking the T-cell response to IL-2 | Impaired wound healing, hyperlipidemia, mouth ulcers, pneumonitis |
| Antimetabolites | Azathioprine (6-MP prodrug), mycophenolate (inhibits IMP dehydrogenase) | Block purine synthesis in lymphocytes | Myelosuppression (TPMT/NUDT15 testing for azathioprine; allopurinol interaction, 11.3); mycophenolate is teratogenic and causes GI upset |
| Glucocorticoids | Prednisone | Broad transrepression | Infection, hyperglycemia, osteoporosis, avascular necrosis, poor healing |
| Costimulation blocker | Belatacept | CTLA-4-Ig variant | Post-transplant lymphoproliferative disorder |
Antineoplastic Agents
| Class | Examples | Mechanism | Toxicities, emphasizing the foot |
|---|---|---|---|
| Alkylating agents | Cyclophosphamide | DNA cross-linking | Hemorrhagic cystitis (acrolein; mesna prevents it), myelosuppression |
| Platinum agents | Cisplatin, oxaliplatin, carboplatin | DNA cross-links | Peripheral neuropathy, nephrotoxicity and ototoxicity (cisplatin), cold-triggered dysesthesia (oxaliplatin) |
| Antimetabolites | Methotrexate, 5-fluorouracil, capecitabine, gemcitabine | Inhibit nucleotide synthesis (5-FU inhibits thymidylate synthase) | Hand-foot syndrome (palmar-plantar erythrodysesthesia: painful erythema and blistering of the palms and soles), mucositis; DPD deficiency causes severe toxicity |
| Microtubule inhibitors | Vincristine (blocks polymerization); paclitaxel, docetaxel (stabilize microtubules) | Mitotic arrest | Chemotherapy-induced peripheral neuropathy (stocking-glove), vincristine ileus, taxane nail changes and onycholysis |
| Anthracyclines | Doxorubicin | Intercalation, topoisomerase II inhibition, free radicals | Cardiomyopathy (dexrazoxane protects); severe necrosis if extravasated |
| Topoisomerase inhibitors | Etoposide (II), irinotecan (I) | DNA strand breaks | Myelosuppression; irinotecan diarrhea |
| Bleomycin | Free-radical DNA cleavage | Pulmonary fibrosis; intralesional use for warts (11.2) | |
| Targeted kinase inhibitors | Imatinib (BCR-ABL); EGFR inhibitors (erlotinib, cetuximab); multikinase inhibitors (sorafenib, sunitinib); BRAF plus MEK inhibitors | Block oncogenic signaling | EGFR inhibitors cause acneiform rash and paronychia with periungual pyogenic granuloma-like lesions; multikinase inhibitors cause hand-foot skin reaction (painful hyperkeratosis at pressure points) |
| Immune checkpoint inhibitors | Pembrolizumab, nivolumab, ipilimumab | Release T-cell brakes | Immune-related adverse events (6.5) |
Tumor lysis syndrome (hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia) is prevented with hydration and allopurinol or rasburicase, which is contraindicated in G6PD deficiency.
Tip
In a patient receiving chemotherapy, burning feet with reduced vibration sense suggests chemotherapy-induced neuropathy. Painful erythema of the soles suggests hand-foot syndrome, and new painful periungual granulation tissue suggests an EGFR inhibitor effect. All three are managed with the oncology team and protective footwear, not by stopping the cancer drug on one's own.
A patient with rheumatoid arthritis on adalimumab every 2 weeks and methotrexate weekly is scheduled for an elective first metatarsophalangeal joint arthrodesis. Which perioperative plan follows the ACR/AAHKS principles commonly extrapolated to foot surgery?
Stop methotrexate 4 weeks before surgery and continue adalimumab on its usual schedule without any change
Stop both drugs 6 months before surgery to allow full immune recovery before the incision
Continue methotrexate; operate at the end of the adalimumab interval and restart it after healing
Continue both drugs on schedule and add stress-dose corticosteroids
A kidney transplant recipient taking tacrolimus is prescribed oral itraconazole for onychomycosis. Which complication is most likely?
Pulmonary fibrosis from free-radical injury
Hemorrhagic cystitis from acrolein accumulation
Acute rejection from markedly lowered tacrolimus levels and reduced immunosuppression
Tacrolimus toxicity (nephrotoxicity, tremor, hyperkalemia) from CYP3A4 inhibition
A patient receiving capecitabine for colorectal cancer develops painful erythema, swelling and blistering of both soles and palms. What is the diagnosis?
Palmar-plantar erythrodysesthesia (hand-foot syndrome)
Dyshidrotic eczema triggered by contact allergy
Keratoderma blennorrhagica from reactive arthritis
Erythema multiforme from herpes simplex reactivation
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