Epidemiology and pathophysiology of osteoarthritis, osteoporosis, gout, and rheumatoid arthritis

Two diseases, clear mechanisms

Two diseases with the clearest mechanism-to-drug mapping in rheumatology
Gout - a metabolic disease with an inflammatory endpoint
- Hyperuricaemia -> crystal deposition -> NLRP3 inflammasome -> IL-1beta
Rheumatoid arthritis - a gene-environment autoimmune disease
- Shared epitope + smoking -> citrullination -> anti-CCP -> synovitis
*In gout you fix the metabolite; in RA you block the cytokine. Neither works the other way round.*

Gout

~1.5-2% of Australians; the commonest inflammatory arthritis in men
M:F ~4:1; rare before puberty and before menopause (oestrogen is uricosuric)
Very high prevalence in Maori, Pacific Islander and Aboriginal and Torres Strait Islander populations
- Genetic urate-transporter variants account for ~60% of the variability in urate handling, usually with otherwise normal kidneys
Rising incidence - tracks obesity, metabolic syndrome, diuretic use and CKD

Rheumatoid arthritis

0.5-1% of adults; F:M ~3:1; peak onset 30-50
Heritability ~60%
Smoking: 20-40x risk when combined with shared epitope, but only for seropositive RA
- Risk stays elevated for ~15 years after quitting
- Smoking also worsens disease course, severity and treatment response

GOUT

### Renal urate handling - where 90% of gout comes from

95-100% of urate is filtered at the glomerulus
~99% reabsorbed in the proximal tubule via URAT1 (SLC22A12) and OAT4
Then secreted, with net excretion of only 5-10% of the filtered load
*The dominant driver of hyperuricaemia is impaired tubular clearance, NOT glomerular underfiltration*

### Causes of impaired urate clearance

Genetic (~60% of variability) - SLC2A9 (GLUT9), ABCG2, URAT1; strongest in Maori/Polynesian populations
Tubular renal disease - lead nephropathy, medullary cystic disease, polycystic kidney disease, cystinuria, analgesic nephropathy
Drugs - thiazide and loop diuretics, low-dose aspirin, ciclosporin and tacrolimus, pyrazinamide, ethambutol, levodopa, teriparatide
Alcohol (also raises lactate -> competes for tubular secretion)
Low urine volume, obesity, hypertension, lactic acidosis, ketosis

### Crystal formation - two requirements

1. Reduced solubility
- A change in urate concentration in either direction - post-surgery, a new diuretic, or starting urate-lowering therapy
- Lower temperature - why the 1st MTP and the ear helix
- Lower pH
- Articular dehydration
- Absence of solubilising factors (proteoglycans)
2. A nucleating seed - cartilage debris, pre-existing OA
This explains why flares cluster around perturbation, not around the highest absolute urate

### The flare

MSU crystals phagocytosed by monocytes/macrophages
-> NLRP3 inflammasome assembly -> caspase-1 -> IL-1beta
-> downstream TNF, IL-6, neutrophil chemotaxis
-> macrophage and osteoclast activation at sites of bone erosion
Self-limiting because of aggregated NET formation and macrophage phenotype switching - hence flares resolve untreated in 7-14 days

RHEUMATOID ARTHRITIS

### Genetic

HLA-DRB1 "shared epitope" - HLA-DR01 and DR04 alleles
- Conserved QKRAA motif in the peptide-binding groove
- Absence of the shared epitope is associated with substantially reduced RA risk
- Homozygosity -> more severe erosive disease
PTPN22 - a T- and B-cell regulatory phosphatase; a missense SNP raises risk of both RA and SLE
The antibody profile maps onto the genotype
- HLA-DR01/DR04 + smoking + PTPN22 -> anti-CCP positivity
- HLA + smoking without PTPN22 -> rheumatoid factor positivity

### Environment -> citrullination

Peptidylarginine deiminase (PAD) converts arginine -> citrulline in mucosal tissue
Triggers: smoking (lung), *periodontitis (Porphyromonas gingivalis, the only bacterium with its own PAD)*, gut dysbiosis, silica
Citrullinated peptides fit the shared-epitope groove -> loss of tolerance -> anti-CCP
Anti-CCP and RF appear years before symptoms - the preclinical window

### Synovitis and destruction

Activated CD4 T cells -> macrophage and B-cell activation
TNF-alpha, IL-6, IL-1 -> synovial hyperplasia, neovascularisation, lymphoid aggregates -> pannus
RANKL -> osteoclast activation -> marginal erosions + juxta-articular osteopenia
MMPs -> cartilage loss -> uniform joint space narrowing
IL-6 additionally drives anaemia of chronic disease (hepcidin), fatigue and the acute phase response

Gout
- Serum urate falls acutely during a flare (~49% normal at presentation) - the acute-phase response is uricosuric
- Negatively birefringent needle crystals - intracellular during a flare
- Normal bone mineralisation on X-ray - there is no systemic inflammatory osteopenia
RA
- Anti-CCP is more specific (~95%) than RF (~80%) and predates onset
- Juxta-articular osteopenia on X-ray - the RANKL signature
- Marginal erosions at the "bare area", where synovium contacts bone without protective cartilage
- Anaemia of chronic disease with raised ESR/CRP - the IL-6 signature

Mechanism	Drug
Gout: urate overproduction	Allopurinol, febuxostat (xanthine oxidase inhibitors)
Gout: URAT1 reabsorption	Probenecid, benzbromarone (uricosurics); losartan and fenofibrate incidentally
Gout: NLRP3 -> IL-1beta	Colchicine (microtubule inhibitor -> blocks inflammasome assembly and neutrophil chemotaxis); anakinra, canakinumab
RA: TNF-alpha	Etanercept, adalimumab, infliximab, golimumab, certolizumab
RA: IL-6	Tocilizumab, sarilumab
RA: T-cell co-stimulation	Abatacept
RA: B cells (CD20)	Rituximab
RA: intracellular JAK-STAT	Tofacitinib, baricitinib, upadacitinib

Gout is curable by fixing the metabolite; RA is suppressible only by blocking the effector cytokine
Smoking cessation is disease-modifying in RA - it lowers risk in relatives and improves treatment response

Gout: metabolic syndrome, CKD, hypertension, heart failure, OSA, myeloproliferative disease, psoriasis, transplantation (calcineurin inhibitors), lead exposure
RA: cardiovascular disease (~4x), ILD, osteoporosis, lymphoma (~3x), depression, infection
Shared: both are associated with excess cardiovascular mortality driven by chronic inflammation
PTPN22 links RA to SLE, type 1 diabetes and autoimmune thyroid disease

Gout: fully modifiable - sustained urate below target dissolves crystal deposits and abolishes flares. Untreated it progresses to chronic tophaceous destructive arthropathy over ~10 years
RA: the preclinical autoantibody phase offers a prevention window under active trial investigation
- The "window of opportunity" - the first ~3 months of symptoms - is when treatment most changes the trajectory
- Untreated, erosions appear within the first 1-2 years
The pathophysiological contrast is the point: gout has a removable substrate, RA has a self-sustaining autoimmune loop

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