Rheumatoid Arthritis

Definition and Overview

Epidemiology

• Prevalence: 0.5-1% in most developed countries; global age-standardized prevalence ~0.25% (Global Burden of Disease 2017).
• Regional variation: Highest in North America, Western Europe, and the Caribbean (0.3-0.4%); lowest in Southeast Asia and Sub-Saharan Africa (~0.1%).
• Special population: Native Americans (Pima and Chippewa tribes) have rates approaching 5-7%.
• Sex ratio: ~3:1 female predominance.
• Peak onset: 4th-5th decade, though it can occur at any age.

Pathogenesis

Genetic Risk Factors

Pre-Clinical Phase

• In seropositive unaffected first-degree relatives of RA patients, subclinical mucosal inflammation is demonstrable
• RA-related autoantibodies occur in diseases characterized by mucosal inflammation (e.g., bronchiectasis)
• ACPA specificity expands in a time-dependent manner pre-clinically, peaking at symptom onset

Citrullination and ACPAs

• Citrullination is a post-translational modification converting positively charged arginine to neutral citrulline, catalyzed by peptidylarginine deiminase (PAD) enzymes (PAD2, PAD4).
• In genetically predisposed individuals, citrullinated proteins trigger autoimmunity.
• Anti-citrullinated protein antibodies (ACPAs) target: collagen type II, fibrinogen, vimentin, and α-enolase.
• The interaction of HLA-DRB1 shared epitope + smoking + periodontitis drives ACPA generation.

Role of Oral Microbiome

Synovial Pathology

• Fibroblast-like synoviocytes (FLS) are activated, producing pro-inflammatory cytokines (TNF, IL-1, IL-6) and matrix metalloproteinases leading to cartilage/bone destruction.
• FLS undergo epigenetic reprogramming (global DNA hypomethylation), acquiring an aggressive, invasive "inflammatory memory" phenotype.
• NETs (Neutrophil Extracellular Traps): Neutrophils are abundant in RA synovium and overexpress PAD2/PAD4. NETs activate FLS, releasing citrullinated autoantigens and perpetuating autoimmunity.

Autoantibodies and Complement

• Rheumatoid factor (RF): IgM (usually) against the Fc portion of IgG.
• ACPAs: More specific than RF; predict aggressive, erosive disease.
• Anti-carbamylated protein (anti-CarP) antibodies: Additional highly specific marker.
• Complement is activated primarily within the joint (via alternative and lectin pathways), with C3a, C5a, and MAC all contributing to synovial inflammation.
• Platelet activation: Thrombocytosis and platelet microparticles are markers of active RA; platelet-leukocyte aggregates, soluble P-selectin, and soluble CD40L are elevated.

Clinical Features

Articular Manifestations

• Symmetric polyarticular inflammatory arthritis involving the small joints of the hands and feet (MCPs, PIPs, wrists, MTPs)
• Prolonged morning stiffness (>1 hour) - cardinal feature
• Swelling, warmth, and tenderness of joints; "boggy" synovitis on exam
• Characteristic deformities (late disease): ulnar deviation at MCPs, swan-neck (PIP hyperextension, DIP flexion), Boutonniere deformity, Z-deformity of thumb
• Large joint involvement (knees, elbows, shoulders, ankles, hips) also occurs
• Cervical spine involvement: atlantoaxial subluxation - important perioperative concern
• Spares DIP joints (distinguishing from OA and psoriatic arthritis)

Extra-Articular Manifestations

Diagnosis and Classification

2010 ACR/EULAR Classification Criteria

Key Laboratory Tests

• RF (rheumatoid factor): Present in ~70-80%; not specific
• Anti-CCP (ACPA): ~70% sensitive, >95% specific; predicts erosive disease
• CRP, ESR: Markers of systemic inflammation
• CBC: Anemia of chronic disease, thrombocytosis
• Imaging: Plain X-rays (erosions, joint space narrowing); MRI/ultrasound more sensitive for early synovitis and subclinical inflammation

Disease Activity Measurement

Management

Principles (Treat-to-Target, T2T)

1. Target: Remission or low disease activity for all patients.
2. Monitor disease activity regularly and escalate therapy if target not met within 3-6 months.
3. The specific DMARD chosen is less important than consistently achieving the target - proven by the TICORA and Dutch BeSt studies.
4. RA can and should be diagnosed early; DMARD therapy should start at diagnosis.

The DMARD Toolbox

• Methotrexate (MTX): The anchor drug; cornerstone of therapy. Titrated up to 25 mg/week; subcutaneous route increases bioavailability. Always given with folic acid supplementation.
• Hydroxychloroquine (HCQ): Used in mild disease or combination (triple therapy with MTX + SSZ)
• Sulfasalazine (SSZ): Often used in combination
• Leflunomide: Alternative to MTX when MTX is contraindicated

• Tofacitinib, Baricitinib, Upadacitinib, Filgotinib
• Oral agents; note safety considerations regarding cardiovascular events and malignancy risk (post-marketing surveillance requirements)

Treatment Algorithm

1. First-line: MTX monotherapy (strongly recommended by ACR/EULAR). If MTX not tolerated, use leflunomide or sulfasalazine.
2. If MTX fails (inadequate response at 3 months, target not met by 6 months): Add a bDMARD or JAK inhibitor to MTX. Choice guided by presence of poor prognostic factors, comorbidities (e.g., avoid JAK inhibitors in high CV risk patients), cost, and patient preference.
3. If first bDMARD fails: Switch to another bDMARD (different mechanism) or tsDMARD.
4. Triple therapy (MTX + HCQ + SSZ) is a cost-effective alternative to bDMARDs in resource-limited settings.

Glucocorticoids

• Powerful, rapidly effective, but carry significant short- and long-term adverse effects.
• Use only as a bridge to DMARD therapy - not as monotherapy.
• Best chronic dose: zero. Always taper once DMARDs are effective.
• Low-dose prednisone (5-10 mg/day) added to MTX reduces disease activity and radiographic progression (CAMERA-II trial).

NSAIDs

• Provide symptom relief but are not disease-modifying.
• Never use without concurrent DMARDs.
• Discontinue once DMARDs achieve disease control.

Tapering and Remission

• DMARD tapering only considered in patients who have achieved sustained remission.
• Drug-free remission remains largely out of reach - at least one DMARD usually must be continued.

Monitoring and Comorbidities

• Cardiovascular risk assessment and management (statins, blood pressure control)
• Bone density monitoring and osteoporosis prevention (especially in glucocorticoid-treated patients)
• Lung disease surveillance (baseline PFTs and HRCT in appropriate patients)
• Infection risk assessment before biologic/JAK inhibitor therapy (TB screening, hepatitis B, live vaccine update)
• Malignancy screening (particularly lymphoma risk)

Prognosis

• RF and ACPA positivity predicts an aggressive disease course with erosive joint damage and extra-articular manifestations.
• Untreated or undertreated RA leads to substantial disability, reduced work capacity, and shortened lifespan.
• With modern T2T strategies and the full DMARD toolbox, the majority of newly diagnosed RA patients can achieve remission or low disease activity - a transformation from the pre-biologic era.

Anterior Pituitary Disorders

Anatomy and the "Master Gland" Concept

Anterior Pituitary Cell Types and Hormones

• Pit-1 (Prop-1): Required for somatotrope, lactotrope, thyrotrope differentiation
• T-Pit: Corticotrope differentiation
• SF-1/DAX-1: Gonadotrope differentiation

Overview of Anterior Pituitary Disorders

1. Hypersecretion - usually caused by a functioning adenoma
2. Hyposecretion (Hypopituitarism) - caused by structural damage, tumors, or developmental defects

I. Pituitary Adenomas

• Cellular monomorphism and absence of a reticulin network (distinguishing from normal gland)
• GNAS gene mutation (constitutive G-protein activation) is among the most common genetic alterations
• Microadenoma: <1 cm - usually does not cause mass effects
• Macroadenoma: ≥1 cm - may invade parasellar structures, compress optic chiasm

Mass Effects of Pituitary Adenomas

• Bitemporal hemianopia - chiasmal compression (classically superior field first)
• Headache (dural stretching)
• Cranial nerve palsies (CN III, IV, VI) from cavernous sinus invasion
• Hydrocephalus (large tumors)
• Hypopituitarism (compression of normal pituitary tissue)
• Pituitary apoplexy: acute hemorrhage/infarction into an adenoma - medical emergency with sudden headache, visual loss, ophthalmoplegia, cardiovascular collapse

Screening Tests for Functioning Adenomas

II. Hyperprolactinemia and Prolactinoma

Physiology of Prolactin

• Normal levels: ~10-25 µg/L (women), 10-20 µg/L (men)
• Prolactin is uniquely under tonic inhibitory control by dopamine (D2 receptor-mediated)
• This explains why stalk section or dopamine-blocking drugs cause hyperprolactinemia
• PRL rises with stress, exercise, meals, coitus, chest wall injury, and markedly during pregnancy (~10-fold)

Causes of Hyperprolactinemia

• Dopamine receptor blockers: antipsychotics (risperidone, haloperidol, phenothiazines), metoclopramide
• Dopamine synthesis inhibitors: alpha-methyldopa
• Opiates, H2 antagonists (cimetidine), SSRIs (fluoxetine), verapamil, estrogens

PRL >200 µg/L almost invariably indicates a prolactinoma. Values <100 µg/L may be caused by microadenomas, stalk compression, or systemic causes.

Prolactinoma: Epidemiology and Presentation

• Most common functioning pituitary tumor (~50% of all); prevalence ~30/100,000 in women, ~10/100,000 in men
• Female-to-male ratio 20:1 for microadenomas; ~1:1 for macroadenomas
• Tumor size correlates directly with PRL level

• Women: amenorrhea, infertility, galactorrhea (amenorrhea-galactorrhea syndrome), loss of libido, osteoporosis
• Men: impotence, loss of libido, infertility, gynecomastia (galactorrhea less common); often present late with macroadenoma and mass effects
• Both: headache, visual field defects (macroadenoma)

Prolactinoma Treatment

• Asymptomatic microadenoma with no fertility desire: observe with serial PRL and MRI
• Mainstay: Dopamine agonists - suppress PRL, shrink tumor, restore gonadal function:
  • Cabergoline (preferred): longer-acting, better tolerated, higher efficacy
  • Bromocriptine: alternative, especially during pregnancy
• After 2 years of normoprolactinemia + significant tumor shrinkage, dopamine agonist may be withdrawn (monitor for recurrence - ~20% of patients)
• Surgery (transsphenoidal): for patients intolerant/resistant to dopamine agonists, or with acute vision loss
• PRL suppression by dopamine agonists does not always confirm prolactinoma (may suppress stalk-compression hyperprolactinemia too without shrinking the mass)

III. Growth Hormone Disorders

Acromegaly (GH excess in adults) / Gigantism (GH excess in children)

• Soft tissue changes: coarsening of facial features, enlarged nose, lips, ears; macroglossia; deep voice
• Acral changes: enlargement of hands and feet (patients note increasing ring/shoe size)
• Prognathism, widened tooth spacing, malocclusion
• Hypertension, cardiomegaly, cardiomyopathy (leading cause of death)
• Diabetes mellitus / insulin resistance (GH is a counterregulatory hormone)
• Sleep apnea, arthropathy, carpal tunnel syndrome
• Colonic polyps (increased cancer risk)
• Gigantism (pre-epiphyseal closure): linear growth acceleration

• Elevated age- and sex-matched serum IGF-1 (best screening test)
• Oral glucose tolerance test (OGTT): GH should suppress to <1 µg/L; failure to suppress confirms autonomous GH secretion
• MRI of pituitary for tumor characterization

• Transsphenoidal surgery (first-line for most)
• Somatostatin analogs (octreotide, lanreotide): inhibit GH secretion; used for residual/recurrent disease or as primary therapy if surgery is high-risk
• Pegvisomant: GH receptor antagonist - normalizes IGF-1 in resistant cases
• Dopamine agonists (cabergoline): modest efficacy
• Radiotherapy: adjunct for persistent disease

GH Deficiency (Adults - AGHD)

• Features: increased body fat (particularly visceral), decreased lean mass, reduced bone mineral density, impaired quality of life, increased cardiovascular risk
• Diagnosis: provocative GH stimulation tests (insulin tolerance test is gold standard; alternatives: arginine, glucagon, GHRH, macimorelin oral test)
• Treatment: GH replacement, starting 0.1-0.2 mg/day, titrated up to 1.25 mg/day; maintain IGF-1 in mid-normal range
• Side effects (~30%): fluid retention, joint pain, carpal tunnel; contraindicated in active neoplasm or uncontrolled diabetes with retinopathy

IV. ACTH Deficiency / Secondary Adrenal Insufficiency

• Glucocorticoid withdrawal (most common - suppression of HPA axis)
• Pituitary adenoma mass effect
• Post-surgical (resection of ACTH-secreting adenoma - indicates cure)
• Rarely: TPIT or POMC mutations

• No hyperpigmentation (requires excess ACTH/MSH - absent in secondary)
• No mineralocorticoid deficiency (aldosterone regulated by renin-angiotensin, preserved)
• Fatigue, weakness, anorexia, nausea, vomiting, hypoglycemia
• Hyponatremia (dilutional - from ADH dysregulation)

• Low morning cortisol + low/inappropriately normal ACTH
• Short Synacthen (cosyntropin) test: impaired cortisol response
• Insulin tolerance test (ITT): most reliable - measures both ACTH and cortisol response to hypoglycemia (contraindicated in seizure disorder, ischemic heart disease, elderly)

V. Cushing's Disease (ACTH-Secreting Adenoma)

• Central obesity, moon face, buffalo hump
• Proximal myopathy, easy bruising, striae (violaceous)
• Hypertension, hyperglycemia/diabetes
• Osteoporosis, poor wound healing
• Hirsutism, menstrual irregularity
• Psychological: depression, cognitive impairment
• Hyperpigmentation (if ectopic ACTH source with very high ACTH levels)

1. Confirm hypercortisolism: 24-h urinary free cortisol, late-night salivary cortisol, 1 mg overnight dexamethasone suppression test (>50 nmol/L = failure to suppress)
2. Confirm ACTH-dependency: plasma ACTH level
3. Localize: High-dose dexamethasone suppression test (pituitary adenoma suppresses; ectopic source does not); CRH stimulation test; pituitary MRI; inferior petrosal sinus sampling (IPSS) - gold standard for confirming pituitary origin and lateralizing tumor

• Transsphenoidal surgery (primary treatment)
• Bilateral adrenalectomy (if pituitary surgery fails - risk: Nelson syndrome with ACTH hypersecretion and hyperpigmentation)
• Medical: ketoconazole, metyrapone, pasireotide (somatostatin analog with affinity for SST5 receptors)

VI. TSH-Secreting Adenoma (Rare)

• Causes central hyperthyroidism: elevated free T4/T3 with unsuppressed or elevated TSH
• Distinguishable from thyroid resistance by MRI showing pituitary mass + elevated alpha subunit
• Treatment: surgery + somatostatin analogs

VII. Gonadotroph Adenomas

• Most common type of clinically non-functioning pituitary adenoma
• Secrete FSH, LH, or alpha subunits inefficiently - usually present with mass effects, not hormonal excess
• Detected incidentally (incidentaloma) or with visual field defects
• Treatment: surgery if symptomatic; observation if small incidentaloma

VIII. Hypopituitarism

Etiology

Order of Hormone Loss in Hypopituitarism (typical sequence)

Clinical Manifestations by Hormone

Pituitary Apoplexy

• Presentation: thunderclap headache, meningism, bitemporal visual field defects, ophthalmoplegia, altered consciousness, cardiovascular collapse
• Management: High-dose glucocorticoids immediately (to treat adrenal crisis); urgent neurosurgical decompression if significant or progressive visual loss/CN palsies; visual recovery inversely correlated with time to surgery

Biochemical Diagnosis of Hypopituitarism

• Low target gland hormone + low or inappropriately normal trophic hormone
  • Low FT4 + low/normal TSH = central hypothyroidism
  • Low testosterone + low/normal LH/FSH = hypogonadotropic hypogonadism
• Provocative tests for GH reserve: ITT, macimorelin test, arginine, glucagon
• Cortisol reserve: ITT (gold standard), CRH test, cosyntropin stimulation

Treatment of Hypopituitarism

• ACTH deficiency: hydrocortisone (15-25 mg/day in divided doses)
• TSH deficiency: levothyroxine (start low, titrate to FT4 in upper-normal range; do NOT use TSH as target)
• LH/FSH deficiency: testosterone (men), estrogen-progesterone (women); gonadotropins for fertility
• GH deficiency: recombinant GH (adults with confirmed deficiency and symptoms)
• Always replace cortisol before thyroid hormone (thyroid hormone increases metabolic rate → can precipitate adrenal crisis if cortisol deficiency uncorrected)

Summary Table: Anterior Pituitary Disorders