DMARDs and Biologics in Rheumatology

Key questions

1. Q1What is rheumatoid arthritis?

   An idiopathic, systemic autoimmune inflammatory arthritis (~1 in 100 people) that erodes joints if untreated.
2. Q2Why use DMARDs rather than just NSAIDs or steroids?

   DMARDs modify the disease — they slow joint damage; NSAIDs and steroids only relieve symptoms (and long-term steroids cause major toxicity).
3. Q3Conventional vs biologic immunosuppression?

   Conventional DMARDs inhibit immune cell production/proliferation (e.g., purine/pyrimidine synthesis). Biologics block individual cytokines or receptors.
4. Q4How many RA patients do well on oral DMARDs?

   About 50%, with single or combination therapy; methotrexate is the cornerstone. Biologics fill in the other 50%.
5. Q5What is a biologic?

   A therapeutic protein derived from living material. It cannot be swallowed — it must be injected (IV, IM, SC) — and it is generally expensive.
6. Q6How is a biologic chosen?

   By diagnosis, effectiveness, cost and toxicity.
7. Q7What do biologic name endings mean?

   -mab = monoclonal antibody; -umab = human; -zumab = humanized; -ximab = chimeric; -cept = fusion receptor; -ra = receptor antagonist; peg- = PEGylated.
8. Q8How is RA classified (2010 ACR/EULAR)?

   Score ≥6 of 10: joint distribution (0–5, more small joints = more points), serology (RF/anti-CCP 0–3), symptom duration ≥6 weeks (1), abnormal CRP/ESR (1).

Key questions

1. Q9What is "treat to target"?

   Use single drugs or combinations with the goal of low disease activity (or remission) and low toxicity, measuring disease activity and adjusting until the target is met.
2. Q10How is RA disease activity measured?

   ACR 20/50/70 responses, DAS28 (tender and swollen joints, CRP/ESR, global health), RAPID3 (patient function, pain, global — no joint count).
3. Q11What is an ACR20 response?

   ≥20% improvement in swollen and tender joints plus ≥20% improvement in 3 of 5: patient global, physician global, pain, ESR/CRP, disability. ACR50/70 = the same at 50%/70%.
4. Q12How well do anti-TNF drugs work in RA?

   About 70% achieve ACR20, 50% ACR50 and 25% ACR70.
5. Q13Is combination therapy better?

   Yes — etanercept plus methotrexate beats either alone.
6. Q14What if a drug never worked (primary failure)?

   Choose another class of drug and review the diagnosis.
7. Q15What if a drug worked, then stopped working (secondary failure)?

   Often anti-drug antibodies: increase the dose or shorten the interval, choose another drug in the class, or choose another target.
8. Q16What are the areas of consensus?

   There is no single best drug; we do not know which drug to start with; no treatment is a bad idea; use some type of DMARD.

Key questions

1. Q17What are anti-drug antibodies (ADAb)?

   Human antibodies against a biologic (a foreign protein) that bind and neutralize it or speed its clearance → reduced or lost efficacy.
2. Q18What raises the risk of ADAb?

   Intermittent (stop-start) dosing, lower doses, not giving a concomitant immunosuppressant, genetic predisposition (e.g., IL-10 polymorphisms), and chimeric (mouse) structure.
3. Q19How do you prevent ADAb?

   Give continuous, regular dosing and co-administer an immunosuppressant such as methotrexate or azathioprine.
4. Q20Which anti-TNF has high vs low ADAb rates?

   Infliximab (IV mouse/human chimeric) — ADAb in 6–61%. Etanercept (human Ig constant + TNF receptor) — much lower.
5. Q21What did early Crohn trials of infliximab show?

   Stop-start dosing triggered by disease activity caused more antibodies and loss of efficacy than regular dosing; immunosuppressants reduced antibodies.
6. Q22Why does pegloticase often fail?

   About 50% of patients form neutralizing antibodies; check serum uric acid — if it is not low, the drug is not working.

Key questions

1. Q23Methotrexate: mechanism, use and toxicity?

   Inhibits dihydrofolate reductase (antimetabolite; low dose also ↑ adenosine). Cornerstone of RA, weekly oral/IM, with folic acid or leucovorin. Toxicity: ↑ liver enzymes (fibrosis rare), cytopenias, lung toxicity (early). Monitor CBC and CMP; avoid in renal insufficiency.
2. Q24Hydroxychloroquine: mechanism, use and toxicity?

   Unclear — raises lysosomal pH, affects TLR signaling. Standard in lupus; used with other agents in RA. Toxicity: retinal toxicity → periodic eye exams.
3. Q25Sulfasalazine: use and toxicity?

   Mechanism unclear; moderately helpful in RA, usually in combination. Frequent sulfa allergy; GI (nausea, vomiting, pain) and CNS (headache, fever, light-headedness); rarer rash, ↑ LFTs, leukopenia/thrombocytopenia, agranulocytosis.
4. Q26Minocycline: mechanism and toxicity?

   Tetracycline; may act on matrix metalloproteinases. Safe but low potency. Toxicity: dizziness, vestibular toxicity, nausea; rarely drug-induced lupus (P-ANCA+, fever, arthritis, skin vasculitis) and hepatitis.
5. Q27Azathioprine: mechanism, use and toxicity?

   Prodrug of 6-mercaptopurine → purine analog incorporated into DNA. Used in lupus, vasculitis, autoimmune lung disease (dropped from RA guidelines 2021). Toxicity: GI intolerance, bone marrow suppression, infections (viral), malignancy.
6. Q28Leflunomide: mechanism, use and toxicity?

   Inhibits dihydroorotate dehydrogenase → ↓ pyrimidine synthesis. Alternative to MTX in RA; no marrow suppression. Hepatotoxic (follow LFTs); very long half-life from enterohepatic recycling → wash out with cholestyramine.
7. Q29Mycophenolate mofetil: mechanism and use?

   Reversible inhibitor of inosine monophosphate dehydrogenase → blocks de novo guanosine synthesis, which lymphocytes depend on. Used for lupus nephritis and transplant; not helpful for RA joints.
8. Q30Anti-TNF drugs: key toxicities?

   Infections, especially TB reactivation (screen with PPD/IGRA first) and hepatitis B reactivation (safe in hepatitis C); possible malignancy; rare drug-induced MS/lupus.
9. Q31Which anti-TNFs work in Crohn disease and uveitis?

   Only the monoclonal antibodies (infliximab, adalimumab, etc.); the fusion receptor etanercept does not. All anti-TNFs help RA and spondylitis joint pain.
10. Q32Rituximab: mechanism, uses and toxicities?

    Anti-CD20 → B-cell depletion for ≥6 months. Used in RA (not psoriatic arthritis or AS), GPA, myositis, lupus, many autoimmune diseases. Toxicity: infusion reactions, PML (JC virus reactivation), hepatitis B reactivation (check HBcAb).
11. Q33Abatacept: mechanism?

    CTLA4-Ig fusion protein that binds CD80/86 on antigen-presenting cells, blocking CD28 T-cell co-stimulation. IV or SC; slow onset, well tolerated, moderately effective in RA.
12. Q34Tocilizumab: mechanism, uses and toxicities?

    Anti-IL-6 receptor. RA refractory to anti-TNF, systemic JIA, giant cell arteritis, Castleman disease, COVID-19 inflammation. Toxicity: infections, ↑ BP, ↑ liver enzymes (and lipids).
13. Q35Anakinra: mechanism, uses and toxicities?

    Recombinant IL-1 receptor antagonist; daily injection. Moderately effective in RA; very effective in periodic fever syndromes (CAPS), systemic JIA/Still disease, acute gout. Toxicity: infections, neutropenia, painful injection-site welts.
14. Q36Tofacitinib: mechanism and toxicities?

    Small-molecule JAK inhibitor (JAK1/3; blocks JAK-STAT cytokine signaling). Approved for RA (also psoriatic arthritis). Toxicity: immune suppression (infections, zoster), ↑ cholesterol. Congenital JAK3 absence causes SCID.
15. Q37Belimumab: mechanism and use?

    Monoclonal antibody against BLyS/BAFF (a B-cell survival factor) → fewer autoreactive B cells. Approved for lupus — helps skin, joints and appears to protect organs/kidneys.
16. Q38Pegloticase: mechanism and problem?

    PEGylated porcine uricase → converts uric acid to allantoin → dramatic fall in serum urate in refractory gout. ~50% develop neutralizing antibodies; monitor serum uric acid.
17. Q39What is IVIG and when is it used?

    Pooled human IgG given IV — replaces antibodies in immunodeficiency and modulates autoimmunity (Fc-receptor blockade, FcRn saturation). Used in Kawasaki disease, ITP, Guillain-Barré, myasthenia crisis and refractory dermatomyositis.
18. Q40What else should you know about the DMARD mechanisms?

    Minocycline is a tetracycline (binds the bacterial 30S ribosome). Methotrexate blocks DHFR → less tetrahydrofolate → less thymidine and purine synthesis → DNA replication stops. Rituximab kills CD20+ B cells by complement-dependent cytotoxicity, ADCC and apoptosis. Anakinra is also used for recurrent inflammatory pericarditis. Tofacitinib's JAK-STAT block stops cytokine-driven differentiation of naïve CD4+ T cells into Th1, Th2 and other subsets.
19. Q41When is cholestyramine given with leflunomide?

    Only after stopping it — to wash the drug out (e.g., before pregnancy or for toxicity), because enterohepatic recycling keeps it around for months.