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Rheumatology and Connective Tissue Diseases Review

Abbreviations and Front Matter

  • Abbreviations are listed on the front index and used throughout the presentation; reference it if you’re unsure about any abbreviation.
  • ANA = antinuclear antibody; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; RF = rheumatoid factor; CCP = anti-cyclic citrullinated peptide; HLA-B27 = human leukocyte antigen B27; DMARD = disease-modifying antirheumatic drug; TNF = tumor necrosis factor; IL = interleukin; JAK = janus kinase; ANCA = antineutrophil cytoplasmic antibody; CREST = calcinosis, Raynaud, esophageal dysmotility, sclerodactyly, telangiectasia.
  • Overview of approach: rheumatologic diseases emphasize pathophysiology and labs; diagnoses grouped to help compare/contrast; focus on signs/symptoms, labs, imaging, and diagnostic criteria; first-line treatments typically DMARDs; many conditions are inflammatory rather than infectious.
  • In synovial fluid analysis, expect inflammatory cell counts and possible crystals depending on diagnosis; septic arthritis is a key infectious differential to rule out.

Overview: Major Themes in the Rheumatology Section

  • Five diagnoses contain the word poly in them and are discussed as a group to highlight similarities/differences; these are seronegative inflammatory/connective tissue diseases (not all with ANA positivity).
  • Serologies: ANA commonly positive in ANA-associated diseases; many seronegative spondyloarthropathies are ANA-negative.
  • Labs and imaging: labs help support but do not solely diagnose; imaging (e.g., X-ray, MRI) and clinical criteria are essential.
  • Treatments: first-line DMARDs (often methotrexate) or NSAIDs for symptomatic relief; escalation to biologics (TNF inhibitors, IL inhibitors) or JAK inhibitors when needed; black box warnings apply to many biologics.
  • Monitoring: assess liver function and other organ systems depending on drug class; pregnancy cautions (e.g., methotrexate unsafe in pregnancy).

Rheumatologic Conditions with ANA Positivity (ANA-associated connective tissue diseases)

Rheumatoid Arthritis (RA)

  • Disease profile
    • Chronic systemic inflammatory disease that targets synovial joints; typically involves small joints of hands/feet in a symmetric polyarticular pattern.
    • Classic presentation: >6 weeks of joint pain in multiple small joints; symmetric involvement.
    • Common deformities: ulnar deviation of the wrist, lateral deviations of fingers, swan neck and boutonnière deformities; spine generally not involved.
    • Pathophysiology: autoimmune inflammatory destruction leads to joint erosion and deformity.
  • Diagnosis and labs
    • Labs are supportive but not diagnostic by themselves; clinical symptoms and timing are essential.
    • ANA: often positive in RA patients, but not specific.
    • RF (rheumatoid factor): positive in about ~80% of RA cases but not specific; can be present in other diseases or be negative in RA.
    • P( ext{RF}^+| ext{RA})
      oughly 0.8
    • Anti-CCP antibody: more specific for RA; still nondiagnostic on its own.
    • ESR/CRP: inflammatory markers that support disease activity.
  • Treatment and management
    • First-line DMARDs: methotrexate (MTX) as the cornerstone.
    • Non-biologic DMARDs (older/established options): methotrexate, sulfasalazine, hydroxychloroquine.
    • Biologic DMARDs (second-line or add-on): TNF inhibitors; IL inhibitors; B-cell or T-cell inhibitors; often used in combination with MTX.
    • JAK inhibitors: newer class ending in -nib (e.g., tofacitinib, baricitinib); used as second/third-line options; share similar black-box warnings.
    • Principles: do not combine two biologics; consider triple therapy with MTX + sulfasalazine + hydroxychloroquine in some studies as non-inferior in certain contexts.
    • Practical notes: MTX generally well-tolerated; monitor liver function tests; MTX is teratogenic; folic acid supplementation reduces MTX toxicity.
  • Practical implications
    • Early aggressive treatment aims to prevent joint destruction and deformity; arm with physical therapy and exercise to maintain function.
  • Juvenile Idiopathic Arthritis (JIA)
    • Pediatric analog of RA; under age 16; joint pains, arthralgias, rashes, fevers, lymphadenopathy possible.
    • Labs: similar supportive labs (RF, anti-CCP, ESR, CRP); ferritin may be elevated in inflammatory states.
    • Treatment: similar to adults; first-line NSAIDs for minor flares and symptoms; MTX as first-line; escalate to biologics if MTX insufficient or not tolerated; avoid chronic corticosteroids in children when possible.

Systemic Lupus Erythematosus (SLE)

  • Disease profile
    • Systemic autoimmune inflammatory disease with wide variability in presentation between patients.
    • Diagnostic criteria require a constellation of findings; any four of the listed items can establish classification.
  • Immunology and diagnostic criteria (MD SOBRAND/A characteristic mnemonic)
    • M: Malar rash (butterfly rash sparing nasolabial folds)
    • D: Discoid rash
    • S: Serositis (pleural or pericardial inflammation)
    • B: Blood disorders (anemia, thrombocytopenia, leukopenia)
    • R: Renal disease (lupus nephritis)
    • A: ANA association (serology positive in most cases)
    • N: Anti-nuclear antibodies + Anti-dsDNA and Anti-Smith antibodies are characteristic immunologic markers
    • D (neuro): Neurologic involvement (e.g., seizures) and other neuropsychiatric manifestations
  • Management and treatment
    • Broad and organ-specific management; use NSAIDs for arthralgias; sun protection is crucial for photosensitivity.
    • Hydroxychloroquine is a common non-biologic DMARD used, with retinal toxicity risk requiring regular eye exams.
    • Immunosuppressive therapies for organ involvement; nephrology involvement for lupus nephritis.
  • Important notes
    • Presentation is highly variable; maintain a high index of suspicion with multi-system involvement.

Sjögren's Syndrome

  • Disease profile
    • Systemic inflammatory autoimmune condition characterized by exocrine gland involvement leading to dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia); may include extra-glandular manifestations such as arthralgia.
  • Autoantibodies
    • Anti-SSA (Ro) and Anti-SSB (La) are characteristic autoantibodies.
  • Management
    • Prednisone can be used for systemic symptoms; non-biologic or biologic DMARDs may be used for refractory disease.
    • Symptom relief: moisturizers for eyes and mouth; artificial tears; saliva substitutes.

Systemic Sclerosis (Scleroderma)

  • Disease phenotype
    • Autoimmune connective tissue disease with two major forms: limited cutaneous (CREST) and diffuse cutaneous.
    • CREST is associated with anticentromere antibodies; diffuse disease may involve anti-Scl-70 (topoisomerase I).
  • CREST features (limited scleroderma)
    • Calcinosis cutis
    • Raynaud phenomenon
    • Esophageal dysmotility (reflux, dysphagia)
    • Sclerodactyly (thickened, painful fingers/toes)
    • Telangiectasia
  • Diffuse disease implications
    • More widespread skin involvement; higher risk of early organ involvement (lung, heart, kidneys).
  • Associated autoantibodies
    • Anticentromere antibodies (CREST)
    • Anti-Scl-70 (topoisomerase I) more common in diffuse disease
  • Organ involvement and complications
    • Pulmonary: interstitial lung disease, pulmonary hypertension
    • Cardiac: cardiomyopathy, arrhythmias, heart failure
    • Renal: renal crisis (hypertension, renal failure)
    • GI: esophageal dysmotility, reflux, other motility issues
  • Management principles
    • No single magic bullet; manage end-organ disease specifically:
    • Reflux/ dysmotility: proton pump inhibitors
    • Renal crisis: ACE inhibitors
    • Raynaud phenomenon: calcium channel blockers
    • Skin: moisturizers and skin-directed care; bracing for joint stability in EDS context (note later section)
    • Lung disease: consider PDE-5 inhibitors for pulmonary hypertension; mycophenolate as an anti-inflammatory agent; oxygen therapy and consideration of lung transplant in advanced disease
    • Mycophenolate mofetil (non-biologic) can help with inflammatory disease; overall prognosis is guarded with significant organ involvement; five-year survival can be reduced relative to general population.
  • Autoantibody summary (quick reference)
    • Anticentromere antibodies: CREST (limited disease)
    • Anti-Scl-70: associated with diffuse systemic sclerosis

Seronegative Vasculitides (Vasculitides affecting vessels of various sizes)

  • Conceptual framework
    • Vasculitis categorized by vessel size: large, medium, and small vessels; each has characteristic clinical features and organ involvement.
  • Large-vessel vasculitis
    • Temporal arteritis (giant cell arteritis) and polymyalgia rheumatica (PMR) are classic large-vessel inflammatory conditions.
    • Temporal arteritis
    • Symptoms: temple/headache pain, jaw claudication, possible transient vision loss (amaurosis fugax)
    • Diagnosis: markedly elevated ESR; temporal artery biopsy confirms diagnosis; start high-dose steroids promptly to prevent vision loss (dosage examples given: substantial steroid courses over 6–12 months, e.g., 60–120 mg prednisone equivalents per day in the acute phase depending on severity)
    • PMR (polymyalgia rheumatica)
    • Elderly patients; neck and shoulder girdle stiffness, fever, malaise, inflammatory symptoms; often coexists with temporal arteritis
    • Lab: elevated ESR/CRP
    • Treatment: NSAIDs for musculoskeletal pain; if temporal arteritis co-occurs, high-dose corticosteroids with temporal artery biopsy confirmation
  • Medium-vessel vasculitis
    • Polyarteritis nodosa (PAN)
    • Symptoms: fever, malaise, skin findings (lived reticularis), lower-extremity ulcerations; renal involvement causing hypertension; peripheral neuropathy
    • Association: ~10% of patients have prior hepatitis B infection; prior/ongoing HBV testing advisable
    • Diagnosis/management: long-term corticosteroids; monitor for systemic involvement
  • Small-vessel vasculitis
    • Granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis)
    • Involves upper and lower respiratory tracts and kidneys; chronic sinusitis, nasal discharge, saddle nose deformity, pulmonary nodules/grays on imaging; hematuria/proteinuria from renal involvement
    • ANCA: c-ANCA positivity often present
    • Treatment: induce remission with rituximab or cyclophosphamide; maintain remission with methotrexate or azathioprine
  • Quick differential and mnemonic cues
    • Large vessels: temporal arteritis; PMR; ESR very elevated; steroids quick to prevent vision loss
    • Medium vessels: PAN; skin and renal manifestations; HBV association
    • Small vessels: GPA; ENT and lung/renal combination; c-ANCA positivity

Crystal Arthropathies and Infectious/Chronic Inflammatory Arthritides

Gout and Pseudogout
  • Gout
    • Etiology: monosodium urate crystals depositing in joints; classic site is the first metatarsophalangeal joint (podagra)
    • Crystal features: needle-shaped urate crystals; negative birefringence under polarized light
    • Acute management: NSAIDs (indomethacin traditionally; other NSAIDs also used) as first-line; colchicine as second-line; corticosteroids as alternative
    • Chronic management: allopurinol to reduce uric acid production; targets hyperuricemia and flare prevention; lifestyle measures (weight loss, low-purine diet, alcohol avoidance)
    • Triggers: thiazide/loop diuretics, niacin can precipitate flares; alcohol and obesity are risk factors
  • Pseudogout (calcium pyrophosphate deposition disease, CPPD)
    • Crystals: calcium pyrophosphate crystals; rhomboid or prism-shaped; positively birefringent under polarized light
    • Affects larger joints (knees, shoulders, ankles)
    • Clinical presentation mirrors gout (acute red, hot, swollen joint) but crystal type differs
  • Diagnostic approach to acute monoarthritis
    • Joint aspiration and synovial fluid analysis:
    • Cell count with differential (often elevated WBCs in inflammatory processes; may be high in septic arthritis as well)
    • Crystal analysis to identify gout or pseudogout crystals
    • Gram stain and culture to exclude septic arthritis
  • Summary of differences
    • Gout: urate crystals; needle-shaped; negative birefringence; treat with NSAIDs, colchicine, steroids; chronic management with allopurinol
    • Pseudogout: CPPD crystals; rhomboid/prism crystals; positive birefringence; treat with NSAIDs or steroids; manage underlying metabolic issues if present
Lyme Disease (Infectious Arthropathy)
  • Etiology and presentation
    • Vector-borne disease from Borrelia burgdorferi; erythema migrans is the characteristic early sign
    • If untreated or inadequately treated, can disseminate (early disseminated disease): meningitis features, pericarditis; very late disease may cause neurocognitive decline
  • Diagnosis and treatment
    • Diagnostic approach: clinical recognition of erythema migrans; serology (ELISA with confirmatory Western blot) or Lyme antibody titers for disseminated disease over time
    • First-line treatment: doxycycline
    • Pediatric/alternative: amoxicillin or cefuroxime for children under 8 or doxycycline intolerance; disseminated disease: ceftriaxone preferred
Fibromyalgia
  • Definition and criteria
    • Chronic widespread pain condition diagnosed by pain in at least 11 of 18 identified trigger points, in the absence of another identifiable cause
    • Course described as nondestructive and nonprogressing
  • Management principles
    • Multimodal approach: sleep optimization, nutrition, mental health support
    • Pharmacologic options include tricyclic antidepressants (amitriptyline, nortriptyline), pregabalin, and duloxetine (SNRI)

Inflammatory Myopathies and Related Conditions

Dermatomyositis and Polymyositis
  • Shared inflammatory pathway; two sides of the same spectrum
  • Polymyositis
    • Proximal muscle weakness (e.g., difficulty rising from chair; shoulder girdle/hip flexors affected)
    • Diagnosis often via muscle biopsy; treatment with corticosteroids; methotrexate as a potential steroid-sparing option
  • Dermatomyositis
    • Similar inflammatory process with characteristic skin findings (heliotrope rash, Gottron papules); may accompany proximal weakness
    • Biopsy for diagnosis; treatment with steroids and methotrexate; skin-directed care and moisturizers important
Polymyalgia Rheumatica (PMR)
  • Clinical features
    • Elderly patients with proximal stiffness and pain of the neck and back; systemic inflammatory symptoms; often coexists with temporal arteritis
  • Laboratory findings
    • ESR and CRP typically elevated
  • Distinguishing from polymyositis
    • PMR features stiffness without true proximal weakness; polymyositis involves muscle weakness with myopathic changes
  • Treatment
    • NSAIDs for neck/back pain; if temporal arteritis is present/possible, high-dose corticosteroids with temporal artery biopsy confirmation; monitor for steroid-related adverse effects

Connective Tissue Disorders and Heritable Conditions

Marfan Syndrome
  • Genetics and key features
    • Autosomal dominant FBN1 gene mutation on chromosome 15; tall stature, chest deformities (pectus), scoliosis; spontaneous pneumothorax; aortic root dilation
  • Management implications
    • Regular echocardiography to monitor aortic dilation; β-blockers or calcium channel blockers to reduce aortic wall stress; activity modification to reduce risk of aortic dissection
Ehlers-Danlos Syndrome (EDS)
  • Inherited collagen-based disorders with multiple types (up to six common variants)
  • Classical features
    • Joint hypermobility with frequent subluxations/dislocations; hyperelastic, easily bruisable skin with poor wound healing
    • Increased risk of aortic root dilation; caution around surgery and implants due to skin/soft tissue fragility
  • Management
    • Activity modification and protective bracing; minimize surgical interventions when possible due to tissue fragility
Osteogenesis Imperfecta (OI)
  • Inherited brittle bone disease
  • Hallmark features
    • Very fragile bones with short stature and growth impairment; history of multiple fractures during childhood; blue sclera in about half of cases
  • Management
    • Activity modification and physical therapy; fracture avoidance strategies; bisphosphonates may be used in some cases to strengthen bone, though evidence varies

Practice Question: Quick Review and Diagnostic Reasoning

  • Scenario: A 71-year-old male presents with bilateral shoulder and buttock pain for six months without prior injury; exam shows no skin changes or range-of-motion deficits.
  • Question: Which lab finding is most likely?
    • Correct answer: Elevated ESR (and inflammatory markers) consistent with polymyalgia rheumatica in an elderly patient with constitutional symptoms and neck/back pain.
    • Rationale: Polymyalgia rheumatica typically presents in older adults with proximal stiffness and systemic inflammatory signs; ESR/CRP are elevated. ANA positivity would be less characteristic here, and HLA-B27 would be more aligned with a seronegative spondyloarthropathy like ankylosing spondylitis in younger patients. Microcytic normocytic anemia is nonspecific in this context.

Quick Distinctions: Summary Mnemonics and Key Truths

  • Ankylosing Spondylitis (seronegative): HLA-B27 associated; morning stiffness improves with movement; bamboo spine is a late finding; anterior uveitis is common; treat with NSAIDs and biologics if needed.
  • Reactive Arthritis (seronegative): post-infection triad (conjunctivitis, urethritis, arthritis); HLA-B27 positive in many cases; treat underlying infection and use NSAIDs/steroids as needed.
  • Psoriatic Arthritis: CASPAR criteria; dactylitis (sausage digits); enthesitis; pencil-in-cup deformity on X-ray; treat psoriasis and arthritis with NSAIDs and DMARDs.
  • Enteropathic Arthritis: associated with Crohn's/UC; often nondeforming; manage Crohn's/UC to control arthritis.
  • Gout vs Pseudogout: crystal analysis essential; gout—needle crystals, negative birefringence; pseudogout—CPP crystals, rhomboid/prism shape, positive birefringence.
  • Large vs Medium vs Small Vessel Vasculitis: big vessels (temporal arteritis/PMR) require prompt steroids to prevent vision loss; medium (PAN) has skin and renal signs; small (GPA) has ENT, lung, and kidney involvement with possible cANCA positivity.
  • Connective Tissue Disorders: Marfan (aortic pathology risk), EDS (tissue fragility), OI (bone fragility and blue sclera).
  • Core Lab-Driven Diagnoses
    • ANA-positive diseases: RA (often ANA positive but not diagnostic), SLE, Sjögren's, Scleroderma, some others.
    • RF and Anti-CCP: RF positive in about 80% of RA; anti-CCP more specific for RA.
    • ESR/CRP: non-specific inflammatory markers used to gauge activity.

Key Takeaways for Exam Preparation

  • First-line treatments in RA are DMARDs, with methotrexate as the initial agent; escalation to biologics or JAK inhibitors when needed; avoid using two biologics together.
  • ANA positivity is common in ANA-associated diseases, but individual tests (RF, anti-CCP) provide added specificity/sensitivity but are not diagnostic alone.
  • Distinguish seronegative spondyloarthropathies from ANA-positive diseases by HLA-B27 status, pattern of joint involvement, and extra-articular features (eye involvement, skin disease, gut disease).
  • Vasculitis classification by vessel size guides presentation and treatment intensity; large-vessel disease requires urgent steroids to prevent organ damage (e.g., vision loss in temporal arteritis).
  • Synovial fluid analysis is crucial in acute monoarthritis to differentiate gout/pseudogout from septic arthritis.
  • Management of systemic diseases often requires multidisciplinary care (e.g., nephrology in SLE with nephritis, rheumatology with GI for enteropathic arthritis, pulmonology for scleroderma-related ILD).

Notes on Drug Safety and Monitoring

  • Methotrexate: hepatotoxicity risk; monitor liver function tests; folic acid supplementation mitigates some toxicity; unsafe in pregnancy.
  • Biologics (TNF inhibitors, IL inhibitors, B-cell/T-cell inhibitors) and JAK inhibitors: share black box warnings for infections and other serious risks; screen for TB before initiation; monitor for infections during therapy.
  • Hydroxychloroquine: retinal toxicity risk; requires regular eye exams; beneficial in SLE and some other ANA-positive diseases.
  • NSAIDs: GI and renal considerations; monitor for adverse effects, especially in older patients.
  • Corticosteroids: broad anti-inflammatory effects but long-term risks (but not detailed here); higher doses and longer courses used in conditions like temporal arteritis.

If you want, I can convert this into a condensed study sheet with a one-page quick-reference for each disease, or we can tailor it to a specific exam format (e.g., multiple-choice practice questions, short-answer prompts).