Overview
This lecture covers the drug treatment of inflammatory joint disease, using rheumatoid arthritis as the model. It sets out what RA is and how it destroys a joint, then works through the three aims of treatment (control pain and symptoms, reduce inflammation, treat disease progression) and the drug classes that serve each: NSAIDs and COX-2 inhibitors, glucocorticoids, xenobiotic DMARDs and biological DMARDs. The unifying idea is that NSAIDs, COX-2 inhibitors and glucocorticoids control symptoms and inflammation but do not alter disease progression, so they act as “bridge” therapy while slow-acting DMARDs take effect, and the lecture ends with the stepwise treatment regime that puts these classes in order.
Learning objectives
- Discuss the difference between Osteoarthritis and Rheumatoid arthritis.
- Understand the rationale for glucocorticosteroid and COX inhibitor treatment in RA, including how steroids and COX inhibitors are used in symptom management and “bridging” in RA.
- Understand the principles underlying the use of Disease Modifying Anti-Rheumatic Drugs (DMARDs) in RA.
- Distinguish between xenobiotic and biological DMARDs.
Rheumatoid arthritis: the disease
- Chronic inflammatory autoimmune disease.
- Prevalence 0.8% worldwide.
- 3 to 5 times more common in females.
- Onset usually between 30 and 55 years old.
- Disabling and painful; about 20 to 30% of patients are unable to work 2 to 3 years after onset.
- Untreated RA is uncommon in the current era; advanced untreated disease shows swollen, deviated and enlarged finger joints (marked hand deformity).
Normal joint versus osteoarthritis versus RA
- Normal joint components: muscle, bone, bursa, synovial membrane, synovial fluid, joint capsule, cartilage, tendon.
- Osteoarthritis: thinned cartilage, so the bone ends rub together.
- Rheumatoid arthritis: swollen inflamed synovial membrane and bone erosion.
Stages of rheumatoid arthritis (in order)
- Healthy joint: bones, cartilage, fibrous capsule, synovial membrane, joint cavity containing synovial fluid.
- Synovitis: synovial membrane inflamed and thickened; bone and cartilage gradually eroded.
- Pannus: extensive cartilage loss, bones exposed and pitted. Pannus is abnormal fibrovascular tissue.
- Fibrous ankylosis: joint invaded by fibrous connective tissue.
- Bony ankylosis: bones fused.
Aims of treatment and the drug classes
Treatment is organised around three aims, with overlap between the first two:
- Control pain and symptoms: paracetamol, NSAIDs.
- Reduce inflammation (overlaps with pain control): NSAIDs, COX-2 inhibitors, glucocorticoids.
- Treat disease progression: DMARDs, subdivided into xenobiotics and biological agents.
Examples given (a sampling):
- NSAIDs: aspirin, ketoprofen, ibuprofen, indomethacin, diclofenac, naproxen.
- DMARDs: methotrexate, cyclophosphamide, gold salts, D-penicillamine, hydroxychloroquine, sulfasalazine.
- COX-2 inhibitors: celecoxib, etoricoxib.
- Immunosuppressants: cyclosporin, leflunomide, azathioprine.
- Glucocorticoids: dexamethasone, prednisone, triamcinolone acetonide.
- Biological agents: infliximab, anakinra, abatacept, rituximab, onercept, etanercept.
The short list to know:
- NSAIDs: ibuprofen, diclofenac.
- COX-2 inhibitors: celecoxib.
- Glucocorticoids: prednisone.
- Xenobiotics: methotrexate, cyclosporin.
- Biological agents: TNF inhibitors (adalimumab, etanercept), IL-6 receptor inhibitor (tocilizumab), CTLA-4 inhibitor (abatacept).
NSAIDs
Mechanism (the eicosanoid pathway)
- Phospholipids of the cell membrane are acted on by PLA2.
- PLA2 releases arachidonic acid.
- COX converts arachidonic acid to PGG2, then to PGH2. NSAIDs block this COX step.
- PGH2 branches to four products: PGE2 (macrophages), PGI2 (endothelial cells), PGD2 (mast cells), TXA2 (platelets).
Common NSAIDs in RA
- Aspirin: irreversible binding, moderately selective for COX-1.
- Ibuprofen: more potent than aspirin, reversible binding of COX-1 and COX-2.
- Diclofenac: more potent than ibuprofen, moderate selectivity for COX-2, available in oral and topical formulations for local anti-inflammatory action.
Role in RA
- All reduce pain and inflammation associated with RA, but do not alter disease progression.
- Useful in the first weeks while the diagnostic workup is underway.
- Used as “bridge” therapy when initiating DMARD treatment, because long-term use carries adverse effects.
COX-2 inhibitors
- Diclofenac is slightly selective for COX-2.
- Coxibs such as celecoxib (Celebrex) are highly COX-2 selective.
- Greatly reduced incidence of GI effects.
- Increased risk of CV events (thrombus formation).
- Prescription only, for symptom control in RA.
Why COX-2 inhibitors raise thrombus risk
- In platelets in the portal circulation, COX-1 produces TXA2, which drives platelet aggregation and vasoconstriction and so promotes thrombus formation. A COX-2 inhibitor leaves this arm unblocked.
- In the vascular endothelium, COX-2 produces prostacyclin (PGI2), which inhibits platelet aggregation and promotes vasodilation, and so inhibits thrombus formation.
- A COX-2 inhibitor reaches the systemic circulation and acts on COX-2 in the vascular endothelium, inhibiting this protective arm.
- Net effect: the protective effect of endothelial COX-2 is lost, increasing clotting.
Glucocorticoids
- Synthesised endogenously by the adrenal cortex.
- Powerful anti-inflammatory and immunosuppressive effects.
- Act by altering gene transcription.
- Limited effects on disease progression, so they are used as “bridge” therapy to control symptoms until DMARDs are effective.
- Glucocorticoids are not a DMARD, precisely because they do not alter disease progression.
Why glucocorticoids combine well with COX inhibitors
- Glucocorticoids upregulate lipocortin-1, which blocks PLA2 and so reduces production of arachidonic acid, upstream of the COX step that NSAIDs block.
- COX-2 is the major mediator of inflammation in the COX pathway, and COX-2 expression is downregulated by glucocorticoids.
- So glucocorticoids reduce both the production of arachidonic acid and its conversion to inflammatory PGE2, which can be reduced further by adding an NSAID, particularly a specific COX-2 inhibitor.
Glucocorticoids in RA
- Prednisone: commonly used for short-term control of flare-ups and acute symptoms of RA. Also used as low-dose long-term therapy where DMARDs have not fully controlled the disease, although this is limited by potential Cushingoid side effects.
- Triamcinolone acetonide: intra-articular injection to treat synovitis (inflammation of the synovial fluid).
DMARDs: general principles
- DMARD = Disease Modifying Anti-Rheumatic Drug.
- Slow acting: weeks to months for onset.
- Decrease disease progression or cause remission.
- All cause immunosuppression, so blood cells must be monitored (WBCs, platelets and so on).
- No analgesic or direct anti-inflammatory effects, so NSAIDs or glucocorticoids are used until DMARD effects appear.
- Some DMARDs work by unknown action; some are used in other conditions as immunosuppressants, for example cyclosporin in transplant patients.
- Immunosuppression can be due to cytotoxicity to dividing cells, or to more targeted effects on the immune system.
- Two groups: cytotoxic agents (also used in chemotherapy), namely methotrexate and cyclophosphamide, and biological agents.
Xenobiotic DMARDs
Methotrexate
- Common first choice DMARD (low cost, effective).
- Used in patients with severe RA, and in some cancers.
- Quicker onset of action than other DMARDs: 3 to 6 weeks.
- Many side effects: mucosal ulceration, hepatic and renal toxicity, skin reactions, nausea, teratogenic.
- Mechanism: folate antagonist; folate is required for production of nucleotides and hence DNA.
- Targets dividing cells: bone marrow cells, progenitor cells in the immune system, tumour cells.
Sulfasalazine
- A prodrug, related to aspirin but with a complex mechanism of action.
- Metabolised into its active components 5-aminosalicylic acid (5-ASA) and sulfapyridine.
- The 5-ASA component helps reduce inflammation in the intestines and joints, while sulfapyridine may contribute to its effects in RA.
- Usually taken orally in tablet form.
- Common side effects: nausea, headache, rash; sometimes more serious effects such as liver problems or blood disorders.
Biological DMARDs
- Target specific signalling pathways between immune cells, which are largely protein-protein (PP) interactions.
- PP binding is complex and generally not targetable by inorganic ligands, but monoclonal antibodies and siRNA (and now emerging, CRISPR) can disrupt PP binding.
- Abatacept: blocks the signal between antigen presenting cell and T cell (listed elsewhere as a CTLA-4 inhibitor).
- Rituximab: depletes B cells.
- Tocilizumab: IL-6 receptor inhibitor.
TNF as a first-line target
- Two strategies: soluble TNF receptor, for example etanercept, and anti-TNF monoclonal antibodies, for example infliximab.
- TNF signalling: TNFα and TNFα/β bind the membrane receptors TNFR1 and TNFR2, and the cascade splits into two arms.
- Survival/transcription arm: through TRADD, TRAF2, RIP, RICK, MADD, I-TRAF/TRAFs, ASK1, NIK, IKK, IκB, NF-κB and JNK to the nucleus, where AP-1/c-Jun and NF-κB drive TNF gene expression and cell survival.
- Apoptosis arm: RAIDD/Caspase1 and FADD/Caspase8, then Caspase8 to Bid to tBid to mitochondria and cytochrome c, to Caspase9, then caspases 3, 6 and 7, then apoptosis.
Warning
The TNF signalling diagram is very dense with many small labelled nodes. The overall pathway structure and major branch points (the survival/NF-κB arm versus the apoptosis arm) are transcribed, but not every minor intermediate label is guaranteed fully legible.
Structures of the TNF-targeting biologics
- Infliximab: mouse variable region plus human IgG1 constant region.
- Adalimumab: human variable region plus human IgG1.
- Etanercept: human TNFR p75 (TNFR2) fused to human IgG1 Fc, with no variable-region arms.
Evidence: continuing versus withdrawing etanercept (PRESERVE trial)
- Kaplan-Meier estimate of time to loss of low disease activity (LDA) plus an increase in DAS28 of more than 0.6, after maintenance, dose reduction or withdrawal of etanercept.
- Etanercept 50 mg + MTX and etanercept 25 mg + MTX both decline gradually and plateau around 55 to 60% by roughly day 400.
- MTX + placebo declines faster and plateaus lower, around 15 to 20% by roughly day 400.
- Interpretation: continued etanercept, with or without dose reduction, maintains disease control substantially better than withdrawal to placebo.
Rituximab as second-line biological therapy
- Used when TNF drugs fail or are contraindicated. Rituximab targets CD20.
- Drug survival data (survival probability versus drug failure or censoring time, log-rank p = 0.0009): the rituximab curve declines much more slowly and settles highest, at about 0.6, while adalimumab, etanercept and infliximab fall to roughly 0.25 to 0.3.
Warning
In the rituximab survival figure the numbers-at-risk table has small dense numerals; the overall trend (rituximab curve highest) is clear, but the individual risk-table counts were not independently re-verified.
Treatment regime
- Patient suspected of having RA. NSAIDs may be given while assessment proceeds.
- Assessment branches to either an alternative diagnosis, or to RA diagnosis confirmed.
- Once RA is confirmed: DMARD therapy, considering glucocorticoids, and NSAIDs can be continued.
- After a period of months, the pathway branches to remission or no remission.
- Remission: taper if glucocorticoids were used, leading to sustained remission.
- No remission: refractory disease, treated with a biological agent or a combination of DMARDs or both, with the options:
- Therapy started with a biological agent if not already started.
- Consider abatacept or rituximab.
- Consider switching to another biological agent.
- Consider enrolment in a clinical trial.
Warning
The right-hand edge of the treatment-regime flowchart sits close to the slide boundary, and the “Alternative Diagnosis” box text may be clipped in the source slide itself, not just in the render.
Self-test
- Define rheumatoid arthritis and give its worldwide prevalence, sex ratio and usual age of onset.
- Distinguish the joint changes of osteoarthritis from those of rheumatoid arthritis.
- Describe the stages of rheumatoid arthritis in order, from healthy joint to end stage.
- List the three aims of RA treatment, with the drug classes used for each.
- Describe the steps of the eicosanoid pathway from cell membrane to prostaglandin products, and state where NSAIDs act.
- Distinguish aspirin, ibuprofen and diclofenac in terms of potency, COX selectivity and reversibility of binding.
- Explain what “bridge” therapy means in RA and why NSAIDs and glucocorticoids are used this way.
- Explain why a highly COX-2 selective inhibitor increases the risk of thrombus formation, and what GI advantage it gives.
- Explain why glucocorticoids combine well with COX inhibitors.
- Why are glucocorticoids not classed as DMARDs, and which two glucocorticoids are used in RA and how?
- List the general principles of DMARD therapy, including onset, effect on disease, shared adverse effect and monitoring requirement.
- Describe the mechanism of action of methotrexate and predict which cell populations are most affected.
- Describe sulfasalazine: what kind of drug it is, its active metabolites, and their roles.
- Distinguish xenobiotic DMARDs from biological DMARDs, and explain why monoclonal antibodies are needed for the biological targets.
- Name the two strategies for targeting TNF, with an example of each, and describe how the structures of infliximab, adalimumab and etanercept differ.
- What did the PRESERVE trial data show about maintaining, reducing or withdrawing etanercept?
- When is rituximab used, and what does it target?
- A patient in whom RA is suspected presents to clinic. Outline the treatment regime from suspicion through to refractory disease, and say at each step which drug classes are in use.
Answers
Reveal answers
- A chronic inflammatory autoimmune disease. Prevalence 0.8% worldwide, 3 to 5 times more common in females, onset usually between 30 and 55 years. It is disabling and painful, with 20 to 30% of patients unable to work 2 to 3 years after onset.
- Osteoarthritis shows thinned cartilage so that bone ends rub together. Rheumatoid arthritis shows a swollen, inflamed synovial membrane and bone erosion.
- Healthy joint; synovitis (synovial membrane inflamed and thickened, bone and cartilage gradually eroded); pannus (abnormal fibrovascular tissue, extensive cartilage loss, bones exposed and pitted); fibrous ankylosis (joint invaded by fibrous connective tissue); bony ankylosis (bones fused).
- Control pain and symptoms: paracetamol, NSAIDs. Reduce inflammation, overlapping with pain control: NSAIDs, COX-2 inhibitors, glucocorticoids. Treat disease progression: DMARDs, both xenobiotics and biological agents.
- Membrane phospholipid, then PLA2, then arachidonic acid, then COX to PGG2 and on to PGH2, which branches to PGE2 (macrophages), PGI2 (endothelial cells), PGD2 (mast cells) and TXA2 (platelets). NSAIDs act at the COX step, blocking conversion of arachidonic acid to the prostaglandin and thromboxane products.
- Aspirin binds irreversibly and is moderately selective for COX-1. Ibuprofen is more potent than aspirin and binds COX-1 and COX-2 reversibly. Diclofenac is more potent than ibuprofen, is moderately selective for COX-2, and comes in oral and topical formulations for local anti-inflammatory action.
- DMARDs are slow acting and have no analgesic or direct anti-inflammatory effect, so NSAIDs or glucocorticoids are used to control pain and inflammation in the first weeks (including while the diagnostic workup is underway) and when DMARD treatment is initiated, until the DMARD takes effect. Long-term NSAID use carries adverse effects, so this is a bridge rather than maintenance.
- Platelet COX-1 continues to make TXA2, which promotes platelet aggregation and vasoconstriction and hence thrombus formation, while the inhibitor reaches the systemic circulation and blocks endothelial COX-2, removing prostacyclin (PGI2), which normally inhibits platelet aggregation and promotes vasodilation. The protective endothelial effect is lost and clotting increases. The advantage is a greatly reduced incidence of GI effects.
- They act at different points of the same pathway. Glucocorticoids upregulate lipocortin-1, which blocks PLA2 and so reduces arachidonic acid production upstream, and they also downregulate COX-2 expression; COX-2 is the major mediator of inflammation in the COX pathway. Adding an NSAID, particularly a specific COX-2 inhibitor, further reduces conversion of arachidonic acid to inflammatory PGE2.
- Because they do not alter disease progression; their effects on progression are limited. Prednisone is used for short-term control of flare-ups and acute symptoms, and in low-dose long-term therapy where DMARDs have not fully controlled disease, limited by Cushingoid side effects. Triamcinolone acetonide is given by intra-articular injection to treat synovitis.
- Slow acting, weeks to months for onset. They decrease disease progression or cause remission. All cause immunosuppression, so blood cells (WBCs, platelets and so on) must be monitored. They have no analgesic or direct anti-inflammatory effects, so NSAIDs or glucocorticoids are used until their effects appear.
- Methotrexate is a folate antagonist; folate is required for production of nucleotides and hence DNA. It therefore targets dividing cells: bone marrow cells, progenitor cells in the immune system and tumour cells.
- A prodrug, related to aspirin, with a complex mechanism of action. It is metabolised into 5-aminosalicylic acid (5-ASA) and sulfapyridine; 5-ASA helps reduce inflammation in the intestines and joints, and sulfapyridine may contribute to its effects in RA.
- Xenobiotic DMARDs are cytotoxic or immunosuppressant small molecules such as methotrexate, cyclophosphamide and cyclosporin, some working by unknown action and some used as immunosuppressants in other conditions such as transplantation. Biological DMARDs target specific signalling pathways between immune cells, which are largely protein-protein interactions; that binding is complex and generally not targetable by inorganic ligands, so monoclonal antibodies and siRNA (and emerging CRISPR) are used to disrupt it.
- Soluble TNF receptor, for example etanercept, and anti-TNF monoclonal antibodies, for example infliximab. Infliximab has a mouse variable region with a human IgG1 constant region; adalimumab has a human variable region with human IgG1; etanercept is human TNFR p75 (TNFR2) fused to human IgG1 Fc, with no variable-region arms.
- Etanercept 50 mg + MTX and etanercept 25 mg + MTX both maintained low disease activity in about 55 to 60% of patients by around day 400, whereas MTX + placebo fell faster to about 15 to 20%. Continued etanercept, with or without dose reduction, maintains disease control substantially better than withdrawal.
- As second-line biological therapy when TNF drugs fail or are contraindicated. It targets CD20 and depletes B cells; in drug survival data it had the highest survival probability, about 0.6, compared with roughly 0.25 to 0.3 for adalimumab, etanercept and infliximab (log-rank p = 0.0009).
- In suspected RA, NSAIDs may be given while assessment proceeds, leading either to an alternative diagnosis or to confirmed RA. Once confirmed, DMARD therapy is started, glucocorticoids are considered, and NSAIDs can be continued. After months the patient either enters remission, in which case glucocorticoids are tapered if used, leading to sustained remission, or does not, which is refractory disease. Refractory disease is treated with a biological agent or a combination of DMARDs or both: start a biological agent if not already started, consider abatacept or rituximab, consider switching to another biological agent, or consider enrolment in a clinical trial.