Rheumatoid Arthritis - Comprehensive Project Report

from reportlab.lib.pagesizes import A4
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import cm
from reportlab.lib import colors
from reportlab.platypus import (
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)
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.platypus import ListFlowable, ListItem

# ── Output path ──────────────────────────────────────────────────────────────
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    title="Rheumatoid Arthritis – Comprehensive Project Report",
    author="Orris Medical AI"
)

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# ── Content ───────────────────────────────────────────────────────────────────
story = []

# ── Cover ─────────────────────────────────────────────────────────────────────
story += [
    Spacer(1, 1.5*cm),
    Paragraph("RHEUMATOID ARTHRITIS", TITLE),
    Paragraph("Comprehensive Project Report", SUBTITLE),
    Paragraph("A complete review of epidemiology, pathophysiology, clinical features,<br/>"
              "diagnosis, treatment, complications and prognosis", SUBTITLE),
    Spacer(1, 0.5*cm),
    HRFlowable(width="80%", thickness=2, color=colors.HexColor("#1a3a5c"),
               hAlign="CENTER", spaceAfter=8),
    Spacer(1, 0.4*cm),
    Paragraph("Sources: Firestein & Kelley's Textbook of Rheumatology • Goldman-Cecil Medicine<br/>"
              "Katzung's Basic and Clinical Pharmacology 16th Ed • Campbell's Operative Orthopaedics 2026<br/>"
              "Murray & Nadel's Respiratory Medicine • Bradley and Daroff's Neurology", SUBTITLE),
    Spacer(1, 0.3*cm),
    Paragraph("Date: July 2026", SUBTITLE),
    PageBreak(),
]

# ── 1. Definition ─────────────────────────────────────────────────────────────
story += [
    h(1, "1.  Definition"),
    hr(),
    p("Rheumatoid arthritis (RA) is a <b>chronic, systemic, autoimmune inflammatory disease</b> "
      "characterized by destructive, <b>symmetric polyarthritis</b> associated with autoantibodies "
      "directed against citrullinated proteins. It is the most common idiopathic inflammatory "
      "arthritis, affecting approximately <b>0.8% of the global population</b>."),
    p("The hallmark pathology is <b>hypertrophic synovitis</b> that leads to joint laxity from "
      "soft-tissue attenuation, progressive cartilage destruction, joint subluxation, and dislocation. "
      "RA is not merely an articular disease — it is a systemic illness with extra-articular "
      "manifestations involving virtually every organ system."),
    Spacer(1, 0.3*cm),
]

# ── 2. Epidemiology ───────────────────────────────────────────────────────────
story += [
    h(1, "2.  Epidemiology"),
    hr(),
    table(
        [Paragraph("<b>Feature</b>", BODY), Paragraph("<b>Data</b>", BODY)],
        [
            [p("Global prevalence"), p("~0.8% of the population")],
            [p("Sex ratio"), p("2–4× more common in women than men")],
            [p("Peak onset age"), p("4th–6th decade (though any age is possible)")],
            [p("Genetic risk"), p("HLA-DRB1 'shared epitope' alleles")],
            [p("Environmental triggers"), p("Smoking, periodontitis, gut microbiome dysbiosis")],
        ],
        col_widths=[W*0.4, W*0.6]
    ),
    Spacer(1, 0.3*cm),
    h(2, "Key Epidemiological Points"),
    b("<b>Smoking</b> increases citrullinated peptides in the alveolar compartment (57% vs 7% "
      "in non-smokers; P<0.05) and upregulates PAD2 enzymes."),
    b("<b>Periodontitis</b> is a significant risk factor — Porphyromonas gingivalis produces "
      "PAD enzymes that generate citrullinated proteins, potentially triggering autoimmunity."),
    b("<b>Gut microbiome:</b> enrichment of Prevotella copri has been demonstrated in patients "
      "with positive autoantibodies and in new-onset untreated RA."),
    b("Risk factors act additively in genetically predisposed individuals; the pre-clinical "
      "phase (positive autoantibodies without joint inflammation) can precede clinical disease "
      "by years."),
    Spacer(1, 0.3*cm),
]

# ── 3. Pathophysiology ────────────────────────────────────────────────────────
story += [
    h(1, "3.  Pathophysiology"),
    hr(),
    h(2, "3.1  Citrullination and Autoantibodies"),
    p("The central molecular mechanism involves <b>citrullination</b> — a post-translational "
      "modification in which positively charged <i>arginine</i> is converted to neutral "
      "<i>citrulline</i> by calcium-dependent <b>peptidyl-arginine deiminase (PAD)</b> enzymes. "
      "In genetically predisposed individuals (particularly HLA-DRB1 shared epitope carriers), "
      "this normally physiological process triggers autoimmunity against citrullinated antigens."),
    p("Several citrullinated autoantigens have been identified: collagen type II, fibrinogen, "
      "vimentin, and alpha-enolase. Smoking, periodontal disease, and HLA-DRB1 polymorphisms "
      "interact to drive ACPA production."),
    Spacer(1, 0.2*cm),
    table(
        [Paragraph("<b>Autoantibody</b>", BODY), Paragraph("<b>Prevalence</b>", BODY),
         Paragraph("<b>Specificity</b>", BODY), Paragraph("<b>Clinical Significance</b>", BODY)],
        [
            [p("Anti-CCP / ACPA"), p("~70%"), p("93–98%"),
             p("Highly specific; may precede symptoms by years; predicts aggressive erosive disease")],
            [p("Rheumatoid Factor (RF)"), p("~75%"), p("Moderate"),
             p("Associated with severe disease and extra-articular features; non-specific (also positive in SLE, Sjögren's, infections)")],
            [p("Anti-carbamylated protein (anti-CarP)"), p("~40%"), p("High"),
             p("Emerging biomarker; relevant in seronegative patients")],
            [p("ANA"), p("~30%"), p("Low"), p("Non-specific; overlap features")],
            [p("pANCA"), p("~30%"), p("Low"), p("Non-specific")],
        ],
        col_widths=[W*0.22, W*0.13, W*0.13, W*0.52]
    ),
    Spacer(1, 0.3*cm),
    h(2, "3.2  Synovial Inflammation — Cellular Events"),
    p("The sequence of events within the inflamed RA joint involves a complex interplay of "
      "innate and adaptive immune cells:"),
    b("<b>Neutrophil influx:</b> Neutrophils flood inflamed joints, especially early synovial "
      "effusions. They overexpress PAD2 and PAD4 enzymes."),
    b("<b>NETosis:</b> Neutrophils form Neutrophil Extracellular Traps (NETs), releasing "
      "citrullinated autoantigens, active PAD isoforms, and NET-derived elastase. NET "
      "complexes correlate with ACPA levels and systemic inflammatory markers."),
    b("<b>Fibroblast-Like Synoviocyte (FLS) activation:</b> NETs activate FLS → release of "
      "pro-inflammatory cytokines (IL-1, IL-6, TNF), chemokines, and adhesion molecules. "
      "FLS also upregulate MHC class II and present NET-derived peptides to CD4+ T cells."),
    b("<b>T and B cell responses:</b> CD4+ T cells drive antigen-specific adaptive responses "
      "and further ACPA production. B cells produce autoantibodies that form immune complexes."),
    b("<b>Pannus formation:</b> The inflamed, hyperplastic synovium (pannus) invades and "
      "destroys adjacent bone and cartilage via activated FLS, macrophages, and osteoclasts."),
    b("<b>Platelets:</b> Thrombocytosis is frequent in active RA (driven by IL-1, IL-6, TNF). "
      "Platelet microparticles harboring CLEC-2 are increased in RA blood."),
    Spacer(1, 0.2*cm),
    h(2, "3.3  Key Cytokines in RA"),
    table(
        [Paragraph("<b>Cytokine</b>", BODY), Paragraph("<b>Role in RA</b>", BODY)],
        [
            [p("TNF-α"), p("Central mediator of synovial inflammation and joint destruction; target of TNF inhibitors")],
            [p("IL-1"), p("Drives bone erosion and cartilage degradation")],
            [p("IL-6"), p("Systemic inflammation, anemia of chronic disease, thrombocytosis, acute phase response; target of tocilizumab")],
            [p("IL-17"), p("Osteoclast activation, bone destruction; produced by Th17 cells")],
            [p("IL-12 / IL-23"), p("T-helper cell polarization toward Th1 and Th17 phenotypes")],
            [p("GM-CSF"), p("Macrophage activation and survival in the synovium")],
        ],
        col_widths=[W*0.2, W*0.8]
    ),
    Spacer(1, 0.3*cm),
]

# ── 4. Clinical Features ──────────────────────────────────────────────────────
story += [
    h(1, "4.  Clinical Features"),
    hr(),
    h(2, "4.1  Articular Manifestations"),
    p("The <b>distribution of involved joints</b> is the most important diagnostic clue. "
      "Symptoms typically begin in the small joints of the hands (PIP and MCP joints) and "
      "the toes (MTP joints). RA <b>characteristically spares the DIP joints</b>, "
      "distinguishing it from osteoarthritis and psoriatic arthritis. Larger joints (wrists, "
      "knees, elbows, ankles, hips, shoulders) are involved later."),
    Spacer(1, 0.2*cm),
    table(
        [Paragraph("<b>Feature</b>", BODY), Paragraph("<b>Description</b>", BODY)],
        [
            [p("Pattern"), p("Symmetric polyarthritis")],
            [p("Small joints first"), p("PIPs, MCPs of hands; MTPs of feet")],
            [p("DIP joints"), p("Usually SPARED")],
            [p("Morning stiffness"), p(">1 hour — a hallmark; proportional to inflammation")],
            [p("Systemic symptoms"), p("Fatigue, weight loss, low-grade fever, malaise")],
            [p("Onset"), p("Usually insidious over weeks to months; rarely acute")],
        ],
        col_widths=[W*0.35, W*0.65]
    ),
    Spacer(1, 0.2*cm),
    h(3, "Classic Hand Deformities"),
    b("<b>Ulnar deviation</b> with MCP palmar subluxation/dislocation — most characteristic deformity"),
    b("<b>Swan-neck deformity</b> — PIP hyperextension with DIP flexion"),
    b("<b>Boutonnière deformity</b> — PIP flexion with DIP hyperextension"),
    b("<b>Mallet deformity</b> — distal interphalangeal hyperflexion (capsular disruption)"),
    b("<b>Attritional tendon rupture</b> — extensor or flexor tendons"),
    b("<b>Z-deformity of thumb</b> — MCP flexion, IP hyperextension"),
    Spacer(1, 0.2*cm),
    h(2, "4.2  Extra-Articular Manifestations"),
    p("RA is a <b>systemic disease</b>. Extra-articular features are more common in seropositive "
      "(RF/ACPA positive) patients with long-standing, poorly controlled disease."),
    table(
        [Paragraph("<b>System</b>", BODY), Paragraph("<b>Manifestation</b>", BODY)],
        [
            [p("Skin"), p("Rheumatoid nodules (20–35%; subcutaneous, over bony prominences), rheumatoid vasculitis, pyoderma gangrenosum")],
            [p("Lung"), p("Interstitial lung disease (ILD), pleural effusions, pulmonary nodules (Caplan syndrome in miners), pulmonary hypertension")],
            [p("Heart"), p("Pericarditis, accelerated atherosclerosis, increased MI/stroke risk, conduction abnormalities")],
            [p("Eyes"), p("Keratoconjunctivitis sicca (Sjögren overlap), scleritis, episcleritis, peripheral ulcerative keratitis")],
            [p("Nervous system"), p("Peripheral neuropathy, cervical myelopathy (atlantoaxial instability), carpal tunnel syndrome, mononeuritis multiplex")],
            [p("Haematological"), p("Normochromic normocytic anaemia of chronic disease; thrombocytosis (active); Felty's syndrome (RA + splenomegaly + neutropenia)")],
            [p("Kidney"), p("Secondary AA amyloidosis (long-standing disease); drug-related nephrotoxicity")],
            [p("Endocrine"), p("Associated with hypothyroidism — check TSH routinely")],
        ],
        col_widths=[W*0.2, W*0.8]
    ),
    Spacer(1, 0.3*cm),
]

# ── 5. Diagnosis ──────────────────────────────────────────────────────────────
story += [
    h(1, "5.  Diagnosis"),
    hr(),
    h(2, "5.1  2010 ACR/EULAR Classification Criteria"),
    p("The 2010 ACR/EULAR criteria replaced the older 1987 ARA criteria, with emphasis on "
      "<b>early diagnosis</b>. A score of <b>≥6 out of 10</b> is required to classify RA. "
      "Entry requirement: at least 1 swollen joint not better explained by another disease."),
    p("If <b>typical RA erosions</b> are present on X-ray, the patient is classified as RA "
      "without needing to score criteria."),
    Spacer(1, 0.2*cm),
    table(
        [Paragraph("<b>Domain</b>", BODY), Paragraph("<b>Criterion</b>", BODY),
         Paragraph("<b>Score</b>", BODY)],
        [
            [p("Joint involvement"), p("1 large joint"), p("0")],
            [p(""), p("2–10 large joints"), p("1")],
            [p(""), p("1–3 small joints"), p("2")],
            [p(""), p("4–10 small joints"), p("3")],
            [p(""), p(">10 joints (including ≥1 small joint)"), p("5")],
            [p("Serology (RF/ACPA)"), p("Both negative"), p("0")],
            [p(""), p("Low positive (≤3× ULN)"), p("2")],
            [p(""), p("High positive (>3× ULN)"), p("3")],
            [p("Acute-phase reactants"), p("Normal CRP and ESR"), p("0")],
            [p(""), p("Abnormal CRP or ESR"), p("1")],
            [p("Symptom duration"), p("<6 weeks"), p("0")],
            [p(""), p("≥6 weeks"), p("1")],
            [p(""), p("<b>MAXIMUM TOTAL</b>"), p("<b>10</b>")],
        ],
        col_widths=[W*0.3, W*0.55, W*0.15]
    ),
    Spacer(1, 0.3*cm),
    h(2, "5.2  Laboratory Investigations"),
    table(
        [Paragraph("<b>Test</b>", BODY), Paragraph("<b>Significance</b>", BODY)],
        [
            [p("Rheumatoid Factor (RF)"), p("Present in ~75%; associated with severe disease; non-specific (positive in SLE, Sjögren's, viral infections, etc.)")],
            [p("Anti-CCP / ACPA"), p("Present in ~70%; HIGHLY SPECIFIC (93–98%); may precede symptoms by years; predicts aggressive erosive disease")],
            [p("ESR / CRP"), p("Elevated in active disease; used to monitor treatment response")],
            [p("CBC"), p("Normochromic normocytic anaemia (chronic disease); thrombocytosis in active disease; cytopenia in Felty's")],
            [p("ANA / pANCA"), p("Each positive in ~30%; non-specific; check for overlap syndromes")],
            [p("Synovial fluid analysis"), p("Inflammatory fluid: WBC 2,000–50,000/μL (predominantly PMNs), low viscosity, high protein")],
            [p("X-ray"), p("Periarticular osteopenia → symmetric joint space narrowing → marginal erosions → deformity/subluxation")],
            [p("Ultrasound"), p("Detects synovitis, tenosynovitis, power Doppler signal — more sensitive than clinical exam in early disease")],
            [p("MRI"), p("Most sensitive for early bone marrow edema, erosions, tenosynovitis; useful when X-ray is normal")],
        ],
        col_widths=[W*0.3, W*0.7]
    ),
    Spacer(1, 0.2*cm),
    p("<i>Note: Approximately 15% of RA patients are <b>seronegative</b> (negative for both RF and ACPA). "
      "These patients generally have milder disease but require exclusion of other diagnoses.</i>"),
    Spacer(1, 0.3*cm),
    h(2, "5.3  Differential Diagnosis"),
    table(
        [Paragraph("<b>Condition</b>", BODY), Paragraph("<b>Key Distinguishing Features</b>", BODY)],
        [
            [p("Viral arthritis (Hep B/C, parvovirus, rubella)"), p("Self-limited (2–3 weeks), specific serology, prodromal viral illness")],
            [p("Systemic Lupus Erythematosus (SLE)"), p("Malar rash, renal disease, ANA+, anti-dsDNA+, photosensitivity, oral ulcers")],
            [p("Psoriatic arthritis"), p("Skin/nail changes, DIP involvement, dactylitis, HLA-B27")],
            [p("Reactive arthritis"), p("Urethritis, conjunctivitis, oral ulcers, HLA-B27, preceding infection")],
            [p("Osteoarthritis"), p("DIP involvement, Heberden's/Bouchard's nodes, non-inflammatory synovial fluid, no systemic features")],
            [p("Chronic tophaceous gout"), p("Urate crystals in fluid, tophi, asymmetric, males, hyperuricaemia")],
            [p("Polymyalgia rheumatica"), p("Elderly, shoulder/hip girdle aching, no synovitis on exam, dramatic response to steroids")],
            [p("Primary Sjögren's syndrome"), p("Sicca symptoms, anti-Ro/La+, less destructive arthritis")],
            [p("RS3PE syndrome"), p("Elderly, seronegative, pitting oedema, abrupt onset — rule out paraneoplastic")],
        ],
        col_widths=[W*0.35, W*0.65]
    ),
    Spacer(1, 0.3*cm),
]

# ── 6. Treatment ──────────────────────────────────────────────────────────────
story += [
    PageBreak(),
    h(1, "6.  Treatment & Management"),
    hr(),
    p("Treatment follows a <b>Treat-to-Target (T2T)</b> strategy. The goal is <b>clinical "
      "remission</b> (or at minimum low disease activity), assessed using validated scores "
      "(DAS28 <2.6, SDAI ≤3.3, or Boolean remission). Early aggressive therapy prevents "
      "irreversible joint damage."),
    Spacer(1, 0.2*cm),
    h(2, "6.1  Non-Pharmacological Management"),
    b("Patient education on disease course, medication adherence, and self-management"),
    b("Physical therapy (range of motion, strengthening exercises) and occupational therapy"),
    b("Splinting and assistive devices to reduce joint stress and maintain function"),
    b("Aerobic exercise and resistance training — safe and beneficial in all stages"),
    b("Smoking cessation — modifies both disease risk and severity"),
    b("Dental hygiene — periodontal disease management reduces inflammatory burden"),
    b("Psychological support — depression and anxiety are significant comorbidities"),
    b("Multidisciplinary team: rheumatologist, physiotherapist, occupational therapist, surgeon, "
      "nurse specialist, dietitian, psychologist"),
    Spacer(1, 0.2*cm),
    h(2, "6.2  Pharmacological Treatment"),
    h(3, "Step 1 — Symptomatic Relief (NSAIDs & Glucocorticoids)"),
    table(
        [Paragraph("<b>Drug Class</b>", BODY), Paragraph("<b>Examples & Doses</b>", BODY),
         Paragraph("<b>Notes</b>", BODY)],
        [
            [p("NSAIDs"), p("Ibuprofen 400 mg QID; Naproxen 500 mg BD; Celecoxib 100 mg BD; Diclofenac/misoprostol"),
             p("Symptomatic relief only — do NOT modify disease. Use with GI protection. Caution in CV/renal disease.")],
            [p("Glucocorticoids"), p("Prednisone ≤10 mg/day PO; Intra-articular triamcinolone"),
             p("'Bridging' therapy while waiting for DMARD effect. Avoid long-term systemic use — osteoporosis, infection, metabolic risks.")],
        ],
        col_widths=[W*0.2, W*0.42, W*0.38]
    ),
    Spacer(1, 0.2*cm),
    h(3, "Step 2 — Conventional Synthetic DMARDs (csDMARDs)"),
    p("<b>Methotrexate (MTX)</b> is the anchor drug and first-line DMARD. Always start here "
      "unless contraindicated. Add folic acid (5 mg/week) to reduce toxicity. "
      "Adjust dose upward to 20–25 mg/week PO or SQ for maximum efficacy."),
    table(
        [Paragraph("<b>Drug</b>", BODY), Paragraph("<b>Dose</b>", BODY),
         Paragraph("<b>Key Points / Monitoring</b>", BODY)],
        [
            [p("Methotrexate"), p("7.5–25 mg WEEKLY (PO or SQ)"),
             p("Anchor drug. Monitor: LFTs, CBC, creatinine. Teratogenic — contraindicate in pregnancy. Avoid alcohol.")],
            [p("Hydroxychloroquine (HCQ)"), p("200–400 mg/day (5 mg/kg)"),
             p("Mild disease; used in triple therapy. Annual ophthalmology review for retinal toxicity.")],
            [p("Sulfasalazine"), p("500 mg OD → 2 g/day (divided doses)"),
             p("Effective alone or in triple therapy. Monitor: CBC, LFTs. Avoid in sulfa allergy.")],
            [p("Leflunomide"), p("10–20 mg OD"),
             p("Alternative to MTX. Very teratogenic — contraindicate in pregnancy/breastfeeding. Long half-life.")],
            [p("Azathioprine"), p("1–2.5 mg/kg/day"),
             p("Alternative when MTX intolerant. Check TPMT before use. Monitor CBC.")],
        ],
        col_widths=[W*0.22, W*0.28, W*0.5]
    ),
    Spacer(1, 0.15*cm),
    p("<i><b>Triple therapy</b> (MTX + HCQ + sulfasalazine) is as effective as biologics in "
      "selected patients and is a valid, cost-effective escalation step.</i>"),
    Spacer(1, 0.2*cm),
    h(3, "Step 3 — Biologic DMARDs (bDMARDs)"),
    p("Used when csDMARDs fail to achieve adequate disease control. Nearly always combined "
      "with methotrexate to prevent immunogenicity. <b>TNF inhibitors are the preferred "
      "first-choice biologics.</b>"),
    Spacer(1, 0.1*cm),
    p("<b>TNF Inhibitors:</b>"),
    table(
        [Paragraph("<b>Drug</b>", BODY), Paragraph("<b>Mechanism</b>", BODY),
         Paragraph("<b>Dose</b>", BODY), Paragraph("<b>Notes</b>", BODY)],
        [
            [p("Etanercept"), p("Soluble TNF receptor fusion protein (p75 + IgG Fc); binds TNF and lymphotoxin"),
             p("50 mg SQ weekly"), p("May be used as monotherapy")],
            [p("Adalimumab"), p("Fully human anti-TNF monoclonal antibody"),
             p("40 mg SQ every 2 weeks"), p("Most widely used TNF inhibitor worldwide")],
            [p("Infliximab"), p("Chimeric (75% human) anti-TNF monoclonal antibody"),
             p("3–5 mg/kg IV at 0, 2, 6 wks → every 4–8 wks"), p("MUST use with MTX to prevent immunogenicity")],
            [p("Certolizumab"), p("PEGylated anti-TNF Fab fragment (no Fc region)"),
             p("400 mg SQ at wks 0,2,4 → 200 mg every 2 wks"), p("Safe in pregnancy (minimal placental transfer)")],
            [p("Golimumab"), p("Fully human anti-TNF monoclonal antibody"),
             p("50 mg SQ monthly"), p("Or 2 mg/kg IV at wks 0, 4, then every 8 wks")],
        ],
        col_widths=[W*0.17, W*0.33, W*0.27, W*0.23]
    ),
    Spacer(1, 0.15*cm),
    p("<b>Non-TNF Biologics (for TNF failure or specific indications):</b>"),
    table(
        [Paragraph("<b>Drug</b>", BODY), Paragraph("<b>Target / Mechanism</b>", BODY),
         Paragraph("<b>Dose</b>", BODY)],
        [
            [p("Tocilizumab"), p("IL-6 receptor antagonist"), p("4–8 mg/kg IV every 4 weeks; or SQ 162 mg weekly/biweekly")],
            [p("Abatacept"), p("T-cell co-stimulation blocker (CTLA4-Ig; blocks CD28–B7 interaction)"),
             p("500–1000 mg IV at 0, 2, 4 wks → every 4 wks")],
            [p("Rituximab"), p("Anti-CD20 monoclonal antibody → B-cell depletion"),
             p("Two 1000 mg IV infusions 2 wks apart → every 16–24 wks (with MTX)")],
            [p("Sarilumab"), p("IL-6 receptor antagonist (anti-IL-6R)"),
             p("150–200 mg SQ every 2 weeks")],
        ],
        col_widths=[W*0.2, W*0.5, W*0.3]
    ),
    Spacer(1, 0.2*cm),
    h(3, "Step 4 — Targeted Synthetic DMARDs (tsDMARDs) — JAK Inhibitors"),
    p("JAK inhibitors are <b>oral</b> targeted agents that block Janus kinase signalling. "
      "They are an alternative to biologics, particularly where injection-related barriers "
      "or specific disease characteristics apply."),
    table(
        [Paragraph("<b>Drug</b>", BODY), Paragraph("<b>JAK Selectivity</b>", BODY),
         Paragraph("<b>Dose</b>", BODY), Paragraph("<b>Special Notes</b>", BODY)],
        [
            [p("Tofacitinib"), p("JAK1/3"), p("5 mg PO BD"), p("First approved JAK inhibitor for RA")],
            [p("Baricitinib"), p("JAK1/2"), p("2 or 4 mg PO OD"), p("Once-daily dosing; also approved for alopecia areata")],
            [p("Upadacitinib"), p("Selective JAK1"), p("15 mg PO OD"), p("Higher selectivity; also used in PsA, AS, AD, UC")],
            [p("Filgotinib"), p("Selective JAK1"), p("200 mg PO OD"), p("Approved in EU; not in US")],
        ],
        col_widths=[W*0.22, W*0.2, W*0.2, W*0.38]
    ),
    Spacer(1, 0.1*cm),
    p("<i><b>Boxed Warning for JAK inhibitors:</b> Increased risk of serious infections, "
      "malignancy, major adverse cardiovascular events (MACE), and venous thromboembolism (VTE), "
      "particularly in patients >50 years with cardiovascular risk factors. Screen and treat "
      "latent TB before initiating.</i>"),
    Spacer(1, 0.3*cm),
    h(2, "6.3  ACR Treatment Algorithm Summary"),
    table(
        [Paragraph("<b>Stage</b>", BODY), Paragraph("<b>Recommendation</b>", BODY)],
        [
            [p("Step 1 (early/low disease activity)"), p("MTX monotherapy (target dose 20–25 mg/week)")],
            [p("Step 2 (inadequate response at 3 months)"), p("Escalate to triple csDMARD therapy OR add TNF inhibitor/non-TNF biologic/JAK inhibitor")],
            [p("Step 3 (biologic failure)"), p("Switch to different biologic class or JAK inhibitor")],
            [p("Remission achieved"), p("Consider cautious tapering (reduce dose, then extend interval) — do not abruptly stop")],
            [p("Poor prognostic features"), p("More aggressive early treatment warranted; consider biologic earlier")],
        ],
        col_widths=[W*0.38, W*0.62]
    ),
    Spacer(1, 0.3*cm),
]

# ── 7. Disease Activity Monitoring ───────────────────────────────────────────
story += [
    h(1, "7.  Monitoring Disease Activity"),
    hr(),
    table(
        [Paragraph("<b>Tool</b>", BODY), Paragraph("<b>Description</b>", BODY),
         Paragraph("<b>Remission Threshold</b>", BODY)],
        [
            [p("DAS28"), p("Disease Activity Score using 28 joints + ESR or CRP + patient global"), p("<2.6")],
            [p("CDAI"), p("Clinical Disease Activity Index — no laboratory values"), p("≤2.8")],
            [p("SDAI"), p("Simplified Disease Activity Index — includes CRP"), p("≤3.3")],
            [p("Boolean remission"), p("Tender joints ≤1, swollen joints ≤1, CRP ≤1 mg/dL, patient global ≤1"), p("All criteria met")],
            [p("HAQ-DI"), p("Health Assessment Questionnaire — measures functional disability (0–3 scale)"), p("<0.5 = minimal disability")],
            [p("Sharp/van der Heijde score"), p("Annual X-ray hands/feet — quantifies erosion and joint space narrowing progression"), p("No change = good")],
        ],
        col_widths=[W*0.2, W*0.55, W*0.25]
    ),
    Spacer(1, 0.2*cm),
    p("Laboratory monitoring should include CBC, LFTs, creatinine, CRP/ESR every 4–8 weeks "
      "initially, then every 3 months when stable. Screen for latent TB and hepatitis B/C "
      "before initiating biologics or JAK inhibitors."),
    Spacer(1, 0.3*cm),
]

# ── 8. Surgical Management ────────────────────────────────────────────────────
story += [
    h(1, "8.  Surgical Management"),
    hr(),
    p("The advent of DMARDs and biologics has <b>significantly reduced</b> the need for "
      "rheumatoid hand surgery. However, surgery remains an important component of "
      "comprehensive disease management when medical therapy is insufficient."),
    Spacer(1, 0.2*cm),
    h(2, "Indications for Surgery"),
    b("Severe joint destruction with pain unresponsive to medical therapy"),
    b("Attritional tendon rupture requiring repair/reconstruction"),
    b("Significant functional impairment affecting activities of daily living"),
    b("Cervical myelopathy from atlantoaxial (C1–C2) instability"),
    b("Nerve compression (e.g., carpal tunnel syndrome unresponsive to splinting)"),
    Spacer(1, 0.2*cm),
    table(
        [Paragraph("<b>Procedure</b>", BODY), Paragraph("<b>Indication</b>", BODY)],
        [
            [p("Synovectomy"), p("Early disease with persistent synovitis, limited erosions, failed medical therapy")],
            [p("Tendon repair/transfer"), p("Attritional extensor or flexor tendon ruptures")],
            [p("Total hip arthroplasty (THA)"), p("End-stage hip RA with pain and functional loss")],
            [p("Total knee arthroplasty (TKA)"), p("End-stage knee RA; PCL-retaining or PCL-substituting designs used")],
            [p("Shoulder/elbow arthroplasty"), p("End-stage glenohumeral or elbow RA")],
            [p("MCP joint arthroplasty (silicone)"), p("Severe ulnar deviation, palmar subluxation, pain")],
            [p("Wrist arthrodesis"), p("Severe wrist destruction; sacrifices motion for pain relief and stability")],
            [p("MTP resection arthroplasty"), p("Forefoot RA with painful metatarsal head subluxation")],
            [p("Cervical spine fusion (C1–C2)"), p("Atlantoaxial instability with myelopathy or high risk of cord injury")],
        ],
        col_widths=[W*0.38, W*0.62]
    ),
    Spacer(1, 0.3*cm),
]

# ── 9. Complications & Prognosis ──────────────────────────────────────────────
story += [
    h(1, "9.  Complications & Prognosis"),
    hr(),
    h(2, "9.1  Articular Complications"),
    b("Progressive joint destruction, deformity, and disability"),
    b("Atlantoaxial subluxation (C1–C2 instability) → risk of sudden cervical myelopathy"),
    b("Joint ankylosis"),
    Spacer(1, 0.2*cm),
    h(2, "9.2  Systemic / Extra-Articular Complications"),
    table(
        [Paragraph("<b>Complication</b>", BODY), Paragraph("<b>Details</b>", BODY)],
        [
            [p("Cardiovascular disease"), p("RA doubles the risk of MI and stroke; equivalent to type 2 DM as a CV risk factor. Main cause of excess mortality.")],
            [p("Interstitial Lung Disease (ILD)"), p("A leading cause of RA mortality; UIP and NSIP patterns most common. More common in seropositive, male smokers.")],
            [p("Infections"), p("Increased susceptibility (disease + immunosuppressive therapy). TB reactivation risk with biologics/JAK inhibitors — screen before use.")],
            [p("Malignancy"), p("Slightly increased risk of Non-Hodgkin lymphoma (proportional to disease activity, not treatment). Reduced solid tumour risk with MTX.")],
            [p("Osteoporosis"), p("From systemic inflammation + corticosteroid use → fragility fracture risk. Screen DEXA; prescribe calcium, vitamin D, bisphosphonates.")],
            [p("Secondary AA Amyloidosis"), p("Rare; from long-standing uncontrolled inflammation. Presents with proteinuria, nephrotic syndrome, renal failure.")],
            [p("Drug toxicity"), p("MTX: hepatotoxicity, pneumonitis; HCQ: retinal toxicity; NSAIDs: GI/renal/CV; Biologics: serious infections, demyelination, CHF.")],
        ],
        col_widths=[W*0.28, W*0.72]
    ),
    Spacer(1, 0.2*cm),
    h(2, "9.3  Prognostic Factors"),
    p("<b>Poor prognostic indicators</b> warrant more aggressive early treatment:"),
    table(
        [Paragraph("<b>Poor Prognostic Feature</b>", BODY), Paragraph("<b>Favourable Feature</b>", BODY)],
        [
            [p("High-titer RF and/or ACPA positivity"), p("Seronegative disease")],
            [p("Early radiographic erosions (<2 years)"), p("No erosions on X-ray")],
            [p("High disease activity at presentation (DAS28 >5.1)"), p("Low initial disease activity")],
            [p("Elevated CRP/ESR"), p("Normal inflammatory markers")],
            [p("Extra-articular features present"), p("Purely articular disease")],
            [p("HLA-DRB1 shared epitope positive"), p("No shared epitope")],
            [p("Female sex"), p("Male sex")],
            [p("Smoking (current or past)"), p("Non-smoker")],
            [p("Low functional status (high HAQ)"), p("Good functional status")],
        ],
        col_widths=[W*0.5, W*0.5]
    ),
    Spacer(1, 0.2*cm),
    p("With modern treat-to-target strategies and early aggressive therapy, <b>remission is "
      "achievable</b> in a significant proportion of patients. Sustained remission may allow "
      "medication tapering. Life expectancy is reduced by approximately <b>5–10 years</b> in "
      "poorly controlled RA, primarily due to cardiovascular disease."),
    Spacer(1, 0.3*cm),
]

# ── 10. Special Forms ─────────────────────────────────────────────────────────
story += [
    h(1, "10.  Special Forms of Rheumatoid Arthritis"),
    hr(),
    h(2, "10.1  Juvenile Idiopathic Arthritis (JIA) — Formerly 'Juvenile RA'"),
    b("Onset before age 16; arthritis persisting >6 weeks"),
    b("Diagnosis by exclusion of other arthritis forms"),
    b("Subtypes: oligoarticular, polyarticular (RF+ or RF–), systemic (Still's disease)"),
    b("Chronic anterior uveitis is a major extra-articular complication — regular slit-lamp screening required"),
    b("Growth disturbances and leg-length discrepancy can occur"),
    Spacer(1, 0.2*cm),
    h(2, "10.2  Felty's Syndrome"),
    b("Classic triad: Seropositive RA + Splenomegaly + Neutropenia"),
    b("Rare; occurs in long-standing seropositive RA"),
    b("Risk of recurrent life-threatening bacterial infections"),
    b("Splenomegaly causes enhanced platelet clearance, but haemorrhage is rare (platelets usually remain >50,000/μL)"),
    b("Large granular lymphocyte (LGL) syndrome can co-occur"),
    Spacer(1, 0.2*cm),
    h(2, "10.3  Seronegative RA"),
    b("~15% of RA patients are negative for both RF and ACPA"),
    b("Generally milder articular disease with fewer extra-articular features"),
    b("Requires exclusion of other seronegative arthropathies (psoriatic, reactive, SpA)"),
    Spacer(1, 0.3*cm),
]

# ── 11. Summary Table ─────────────────────────────────────────────────────────
story += [
    h(1, "11.  Summary — Quick Reference Table"),
    hr(),
    table(
        [Paragraph("<b>Feature</b>", BODY), Paragraph("<b>Rheumatoid Arthritis</b>", BODY)],
        [
            [p("Type"), p("Chronic systemic autoimmune inflammatory arthritis")],
            [p("Prevalence"), p("~0.8% globally; F:M = 2–4:1")],
            [p("Key autoantibodies"), p("RF (~75%), ACPA/anti-CCP (~70%)")],
            [p("Central mechanism"), p("Citrullination → ACPA generation → synovitis → pannus")],
            [p("Joint pattern"), p("Symmetric, small joints (MCPs, PIPs, MTPs); spares DIPs")],
            [p("Hallmark symptom"), p("Morning stiffness >1 hour")],
            [p("Classic deformity"), p("Ulnar deviation, swan-neck, boutonnière")],
            [p("Diagnosis criteria"), p("2010 ACR/EULAR — score ≥6/10")],
            [p("Anchor drug"), p("Methotrexate (weekly dosing)")],
            [p("1st-line biologic"), p("TNF inhibitors")],
            [p("Oral targeted therapy"), p("JAK inhibitors (tofacitinib, baricitinib, upadacitinib)")],
            [p("Treatment target"), p("Clinical remission (DAS28 <2.6)")],
            [p("Main cause of death"), p("Cardiovascular disease; interstitial lung disease")],
            [p("Life expectancy impact"), p("Reduced by ~5–10 years if poorly controlled")],
        ],
        col_widths=[W*0.35, W*0.65]
    ),
    Spacer(1, 0.5*cm),
]

# ── Sources ───────────────────────────────────────────────────────────────────
story += [
    h(1, "References & Sources"),
    hr(),
    Paragraph("All content sourced from authoritative medical textbooks:", SOURCE),
    Paragraph("1. Firestein GS & Kelley WN. <i>Firestein & Kelley's Textbook of Rheumatology</i>, "
              "2-Volume Set. Elsevier.", SOURCE),
    Paragraph("2. Goldman L & Schafer AI. <i>Goldman-Cecil Medicine International Edition</i>, "
              "2 Volume Set, Chapter 243. Elsevier.", SOURCE),
    Paragraph("3. Katzung BG. <i>Basic and Clinical Pharmacology</i>, 16th Edition, Chapter 36. "
              "McGraw-Hill.", SOURCE),
    Paragraph("4. Azar FM et al. <i>Campbell's Operative Orthopaedics</i>, 15th Ed 2026. Elsevier.", SOURCE),
    Paragraph("5. Broaddus VC et al. <i>Murray & Nadel's Textbook of Respiratory Medicine</i>, "
              "2-Volume Set. Elsevier.", SOURCE),
    Paragraph("6. Daroff RB et al. <i>Bradley and Daroff's Neurology in Clinical Practice</i>. Elsevier.", SOURCE),
    Paragraph("7. Hochberg MC et al. <i>Rheumatology</i>, 2-Volume Set (2022). Elsevier.", SOURCE),
    Spacer(1, 1*cm),
    Paragraph("Report generated by Orris Medical AI | July 2026", SUBTITLE),
]

# ── Build ──────────────────────────────────────────────────────────────────────
doc.build(story)

from pypdf import PdfReader
reader = PdfReader(OUTPUT)
print(f"PAGES: {len(reader.pages)}")
print(f"FILE: {OUTPUT}")