Connective Tissue Disease

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    Systemic Lupus ErythromatosisEdit section

    Symptoms/Diagnosis

     

    • SOAP BRAIN MD - Need 4/11 to diagnose lupus
    • Criteria for diagnosis:

      MD SOAP BRAIN (NEED 4/11 TO DX)
      ## Criteria Description
      1  M - Malar Rash "Butterfly Rash", sparing nasolabial folds, no scarring
      2  D - Discoid Rash May cause scarring (invades basement membrane)
      3  S - Serositis Pericarditis, Pleuritis
      4  O - Oral/nasal Ulcers Usually painless
      5

       A - ANA positive

      98% sensitive, not specific.
      6  - Photosensitivity Skin rash in reaction to light
      7  B - Blood Hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia
      8  R - Renal Proteinuria (>0.5g/day or 3+).  Cell casts (RBC, Hb, granuar, tubular, mixed)
      9  A - Arthritis Symmetric, involving ≥2 small or large peripheral joints, non-erosive (unlike RA)
      10  I - Immune Anti-dsDNA, anti-Sm, anti-Ro/La, APA (anticardiolipin Ab, Lupus anticoag)
      11  N - Neuropsychiatric Seizures/psychosis

       
    • Ask other things too:
      • Losing weight, fevers, night sweats
      • Blood clots
      • Miscarriages
      • If known: Are flairs concordant with serology?
      • Is there renal involvement?

    Labs

    • ANA
      • Most sensitive 95% (used to rule out)
      • Non-specific
      • ANA titres not followed with disease course
    • Anti-DNA & Anti- Sm  (95-99% specific)
    • Monitor treatment with:  (only if serologically concordant)
      • Anti-DNA tires (increase with flair)
      • C3, C4  (decrease with flair)
    • Anti-Phospholipid ab (Anti-cardiolipin Ab and Lupus anticoagulant
      • May cause increased thrombosis and aPTT
    • Others:
      • Anti-Ro  (Sjogren's) or anti-La (SSB)
      • Anti-Histone Ab (Drug-induced lupus)

    CauseEdit section

    • Production of auto-antibodies causing multi-organ inflammation
    • Multifactorial:
      • Genetics (HLA-B8/DR3 ~10% have positive family hx)
      • Estrogen
        • Pre-pubertal and post-menopausal women have higher incidence than men.
        • Men with SLE have higher concentration of estrogenic metabolites
        • F:M = 10:1
      • Infection (viral - non-specific immune simulant)
      • Drug-Induced:  (See Anti-histone antibodies)
        • Anti-convulsants (Phenytoin)
        • Anti-hypertensives (Hydralazine)
        • Anti-Arrhythmics (Procainamide)
        • Isoniazid (INH)
        • Biologics
        • OCP (associated with exacerbation

     

    Organ Involvement

    • Systemic - fatigue, malaise, wt loss, fever
    • Renal - HTN, peripheral edema, GN, renal failure.
    • Derm - Photosensitivity, malar rash, discoid rash, oral alcers, alopecia.
    • MSK - Polyarthralgias, polyarthritis, myalgias, AVN
    • Opthalmic - Keratoconjunctivitis sicca, episcleritis, scleritis
    • Cardiac - Pericarditis, CAD, non-bacterial endocarditis (Libman-Sachs) (risk factor for CAD)
    • Vascular - Raynaud's phenomenon, livedo reticularis, thrombosis, vasculitis
    • Resp - Pleuritis, ILD, PE, etc.
    • GI - Pancreatitis, lupus enteropathy.
    • Neurologic - headache, depression, psychosis, seizures

     

    Disease Activity Index

    • Many!
    • SLEDAI - SLE Disease Activity Index
    • SLAM  - Systemic Lupus Activity Measure
    • BILAG - British Iles Lupus Assessment Index
    • Pros/cons for each, many trials do more than one

     

    • HAQ - Health Assessment Questionaire 
      • Purely functional, patients fill out. (walking, grooming, etc..)
      • Measure of disease activity AND damage
      • Prognostic
      • Short Version of HAQ: multidimensional HAQ, Rapid 3, etc...  (many useful + practical)

     

    Treatment

    • Goals:
      • Treat early, avoid long term steroid use (if possible)
      • If high doses needed for long-term control, add steroid sparing agent and taper when possible.
      • Treatment tailored to organ system involvement and tailored to severity.
      • All medications used to treat SLE need monitoring for toxicity
    • Dermatologic
      • Sunscreen, avoid UV light and estrogens.
      • Topical steroids, hydroxychloroquine
    • MSK
      • NSAIDs ± gastroprotection   (arthritis, pleuritis, pericarditis)
      • Hydroxychloroquine improves long-term control, prevents flairs
      • Bisophosphonates, Calcium, Vitamin D (osteoporosis)
    • Organ-Threatening Disease
      • High-dose Oral Prednisone or IV methylprednisolone in severe disease.
      • steroid-sparing agents: azathioprine, methotrexate, mycophenolate.
      • IV cyclophosphamide for serious organ involvement (e.g. cerebritis or SLE nephritis)

     

    Sjogren's Syndrome

    Definition

    • Autoimmune condition characterized by lymphotytic infiltration of salivary and lacrimal glands.
      • Dry eyes (keratoconjunctivitis sicca/xerophthalmia)
      • Dry mouth (xerostomia)
      • May be systemic involving:
        • Exocrine glands
        • Respiratory glands
        • Skin
    • Can be:
      • Primary
      • Secondary associated with:
        • RA, SLE, DM, HIV

    Diagnosis

    • Need 4 of:
      • Criteria (need 4/6
        Incl. one of BOLD)
        Description
        1. Dry eye symptoms >3mo of foreign body sensation, requiring tear substitutes
        2. Dry mouth symptoms >3mo of swollen salivary glands requiring liquids to swallow food
        3. Dry eye signs Schirmer test (tear flow) or slit lamp with Rose Bengal stain
        4. Dy mouth signs Low salivery flow (saliography)
        5. Salivary gland biopsy Focal lymphocytic sialoadenitis
        6. Autoantibodies anti-Ro, and/or anti-La, ANA, RF
      • "sicca complex": dry eyes, dry mouth
      • Infection: staph blepharitis, dental caries, oral candidiasis, angular cheilitis (inflam. of mouth labial fissures).
      • Systemic Features:
        • Sinusitis, autoimmune thyroid dysfunction.
        • Arthralgias/arthritis
        • Interstitial lung disease, xerotrachea --> chronic dry couth.
        • Renal: Interstitial Nephritis (unclear if causes glomerular disease)
        • Vasculitis: palpable purpura
        • Peripheral neuropathy
        • Lymphoma risk is high.

    Treatment

    • Ocular
      • Artificial tears
      • Surgical punctal occlusion (prevent drainage from eye)
      • Cyclosporine Drops
    • Oral
      • Hydration, Dental Hygeine
      • Pilocarpine: stimulates salivary flow
      • Oral Candidiasis
        • Topical nystatin or clotrimazole.
    • Systemic Involvement
      • Hydroxychloroquine, corticosteroids  (are not good for sicca symptoms)
      • (No role for TNF-alpha inhibitors - failed to improve symptoms)

    Scleroderma

    • Non-inflammatory disorder --> widespread small vessel vasculopathy + fibrosis in the setting of autoimmunity.
      • Vasculopathy (not vasculitis) leads to atrophy/fibrosis of tissues.
      • Intimal proliferation and media mucinous degeneration --> progressive obliteration of vessel lumen --> leading to fibrotic tissue.
      • (similar to malignant hypertension)
    • SclerodermaApproach2.png

    Diagnosis

      • 1 major or 2 minor criteria
        • Major:
          • Scleroderma proximal to MCPs (Skin tightening, thickening, non-pitting induration)
        • Minor
          • Sclerodactyly (skin changes limited to digits)
          • Digital pitting scars or loss of substance from finger pad
          • Bibasilar pulmonary fibrosis
    • Blood work:
      • CBC, Creatinine,
      • ANA is positive in 70%
      • Anti-Topoisomerase 1 / anti-Scl-70: Diffuse systemic sclerosis (specific, non-sensitive)
      • Anti-Centromere (limited systemic sclerosis - CREST)
    • Imaging
      • YEARLY CXR for fibrosis
      • YEARLY Echo for pulmonary HTN

     

    Symptoms/Manifestations

    • Mostly MSK manifestations, but many other organs can be affected:
      • Puffiness, tightness of skin overlying hands
      • Dilated nailfold capillaries (strong predictor of scleroderma)
      • Tendon Rubs (very strong indicator of systemic sclerosis)
      • Raynaud's Phenomena
    •  
    • System Findings
      Dermatologic

      - Skin itching (esp in diffuse systemic) - first manifestation

      - Skin tightening (painless non-pitting edema)

      - Ulcerations, calcinosis, periungal erythema, hypo/hyperpigmentation, pruritis, telangiectasias

      Scleroderma1.jpeg  scleroderma3.jpg  scleroderma4.jpg

      Vascular Raynaud's Phenomenon, Digital pits, Gangrene

      Gastrointestinal

      (~90%)

      - Dysphagia (distal esophageal hypomotility)

      - GERD/ulcerations/structures (Loss of LES sphrincter function)

      - Small bowel hypomotility --> bacterial overgrowth, diarrhea, bloating, cramps, malabsorption, wt loss

                                    (Classicaly B12 deficiency, folate excess - bacteria consume B12, make folate)

      - Large bowel hypomotility --> wide mouth diverticuli (on barium study)

       

      Renal

      - Mild proteinuria  (mild creatinine elevation, hypertension)

      - "Scleroderma Renal Crisis" (10-15%): malignant hypertension, oliguria, MAHA anemia

      Pulmonary Intestitial fibrosis, pulmonary HTN, pleural effusions
      Cardiac LV dysfunction, pericarditis, pericardial effusion, arrhythmias
      MSK

      Polyarthralgias

      Tendon Rubs (very strongly predicts diffuse systemic sclerosis)

      "Resorption of distal tufts" (radiology finding)

      Myositis

      Proximal muscle weakness 2° diffuse atrophy and low grade myopathy

      Endocrine (Hypothyroidism)

     

     

    Treatments

    • No disease-modifying agents available. 
    • Treat symptoms
    • Inflammatory manifestations (myositis, arthralgias/arthritis)
      • Avoid steroids (can precipitate scleroderma renal crisis)
        • Although low-dose can be used for some things like itching
      • Hydroxychloroquine (for joint pain)
      • Methotrexate (more potent than HCQ, helps more myositis)
    • Avoid NSAIDs - can exacerbate renal crisis, HTN, worsening renal function
    • Others:
      • Manifestation Treatment
        Dermatologic (itching, tightening) Skin hygeine, can consider low-dose steroids or MTX (poor evidence)
        Raynaud's Phenomenon

        Non-Pharmacologic

          - Mittens, heating pads

        Pharmacologic

          - Vasodilators (CCB, Nitrate paste)

            Sildenafil, Nifedapine/Amlodipine

        Last Line
          ADMIT + IV Alprostadil (prostacyclin analogue) x72hrs on monitor. 

         

        GERD PPI first line (H2-antagonists can be used)
        Small Bowel Bacterial Overgrowth Antibiotics (tetracycline, metronidazole)
        Hypertension/Renal Crisis ACE inhibitors
        Pulmonary

        Alveolitis - Cyclophoshamide

        Interstitial Lung Disease -  ?? 

        Pulmonary HTN - Vasodilators (bosentan, epoprostenol)

        Pericarditis  
    • Notes:
      • Cyclophosphamide tried (no long-term benefits)
    • Follow-Up:
      • Rheumatologist Referral
      • Frequent bloodwork (monitor esp. renal function)
      • Frequent HTN follow-up (if rises need ACE inhibitor)
      • YEARLY PFTs (r/o ILD)
      • YEARLY CXR
      • YEARLY Echo (r/o pulmonary HTN, catch+treat early)

     

    Scleroderma Renal Crisis

    • Potentially life threatening condition
    • Occurs in 10-15% of pts with systemic sclerosis
    • Normal BP in 10% of pts.
    • Pathophysiology
      • Vascular involvement of affertent arterioles leads to glomerular ischemia and hyperreninemia.
    • Symptoms:
      • Oliguric kidney disease
      • Severe hypertension
      • Mild proteinuria... Urinalysis with few cells or casts
      • MAHA (thrombocytopenia)
      • Sometimes:
        • Pulmonary Edema
        • Hypertensive Encephalopathy
    • Diagnostic Criteria:
    1. Acute onset Renal Failure
    2. Abrupt onset of moderate to marked hypertension (although some are normotensive)
    3. Urine sediment is normal (or mild proteinuria with some casts). 
    • Management:
      • First Line: ACE inhibitors to control malignant hypertension is cornerstone of management.
        • Can stabilize or even improve renal function in up to 55% to 70% of cases
        • Captopril recommended (titratable due to short half-lfie, and most studied)
      • IV BP meds (i.e. labetalol & nitroprusside) avoided, decrease BP too fast, can coase worse AKI & even ATN.

    Inflammatory Myopathies

    Polymyositis / Dermatomyositis

    Source:MKSAP 16 question

    Intro

    • PM is CD8 T-cell mediated muscle necrosis (in adults) [same as inclusion body myositis]
    • DM is a B-cell and CD4 immune complex mediated peri-fasicular vasculitis
      • Same symptoms of PM, but has an extra rash
    • Can be associated with other connective tissue diseases:
      • SLE
      • Systemic Sclerosis
      • Mixed CTD
    • Paraneoplastic

     

    Diagnosis

    • Criteria:
      • Definite if 4 present
      • Probable if 3 present
    • Criteria Description
      1. Symmetric proximal muscle weakness Typical shoulder girdle and hip girdle
      2. Elevated muscle enzymes High CK, aldolase, LDH, AST, ALT
      3. EMG changes

      Short polyphasic motor units, high frequency repetitive discharge

      Insertional irritability

      4. Muscle biopsy

      Segmental fibre necrosis, basophilic regeneration, perivascular

      inflammation (DM), endomysia inflammation (PM), atrophy

      5. Typical Rash of Dermatomyositis Required for DM diagnosis.

    Symptoms

    • Progressive symmetrical proximal muscle weakness (shoulder and hip) developing over weeks to months.
      • Most difficult lifting head from pillow, arising from chair, climbing stairs.
      • Little to no pain
    • Dermatological (DM ONLY!)
      • Photosensitive rash over face, chest, hands.
      • Heliotrope rash - violaceous rash over eyelids; usually with edema.
      • Gottron's papules - Pink-violaceous, flat-topped papules overlying the dorsal surface of the DIP and PIP points. 
      • Gottron's sign - Erythematous, smooth or scaly papules over extensor surfaces of joints.
      • Shawl sign - erythematous rash over neck, upper chest, and shoulders. (looks like sunburn)
      • Mechanic's hands - roughened erythematous, hyperkeratotic fissuring of palmar and lateral fingers.
        • dark, dry, thick scale on palmar and lateral surface of digits.
      • Periungal erythema & telangenctasias
    • MSK
      • Muscle symptoms can be subclinical - and pts just get a rash (some show no muscle inflammation)
    • Cardiac
      • Dysrhythmias, CHF, conduction defects, ventricular hypertrophy, pericarditis.
    • GI
      • Oropharyngeal and esophageal dysphagia, reflux.
    • Pulmonary
      • Weakness of resp muscles, ILD, aspiration pneumonia.

    Investigations

    • Bloodwork: CK, ANA (80% positive), anti-Jo-1 (DM) anti-Mi-2, anti-SRP
    • EMG, muscle biopsy

    Treatment

    • Check for Extramuscular involvement (fever, weight loss, cardiac/GI/pulmonary)
    • Pharmacologic
      • High dose steroids x~4weeks  (1-2mg/kg/day) until CK levels normalize, then slow taper
        • If severe, IV pulse steroids
        • Baseline bone mineral density, Ca, Vitamin D, bisphosphonates.
      • IV IgG if severe/refractory (given in addition to steroids, or if steroids contraindicated)
      • Hydroxychloroquine for DM rash
      • Add immunosuppressive agents (azathioprine, methotrexate, cyclosprine) for:
        • Add to steroids for severe disease (extramuscular/cardiovascular/pulmonary involvement)
        • Add to steroids for steroid-resistant disease
        • Steroid sparing therapy
    • Non-Pharmacologic  (very important for inflammatory myopathyies)
      • Physio, occupational therapy
      • Exercise (does not raise CK levels)
    • Malignancy Surveillance
      • Associated with DM
        • Breast Ca
        • Lung Ca
        • Colon Ca
        • Ovarian Ca
    • Recommended: Yearly pulmonary function testing for mod-to-severe disease:
      • check DLCO --> high risk of interstitial lung disease, may need high res CT.

    Inclusion Body Myositis

    • Very slowly progressive - weakness of both proximal and distal muscles
      • Quads, wrists, finger flexors, swallowing
      • Typically symmetric, can be asymmetric in up to 15% of cases.

    Mixed Connective Tissue Disease (MCTD)

    • MCTD is an overlap syndrome of:
      • Systemic scleroderma
      • SLE
      • Myositis
    • Commonly Raynoud's phenomenon, swollen fingers.
    • Cardiac involvement is common
    • Bloodwork: anti-RNP
    • Prognosis:
      • 50-60% will evolve into SLE
      • 40% will evolve into scleroderma
      • 10% will remain as MCTC entire life

     

     

    Raynaud's Phenomena

    • Ischemia in distal digits
    • Causes: (many!)
      • Connection Tissue Disease: SLE, Scleroderma, MCTD
      • Repeated Mechanical Vibrations (i.e. jack-hammer, sanding etc..)
      • Burger's Disease (smoking related)
    • Approach
      • Perform labs + focused history/physical to rule out connective tissue disease
      • (ANA, ENA Panel, Complements, CBC, Lytes, Creat, Urea, ESR, CRP, Urine Dip etc...)
      • If nothing found --> manage conservatively (often rheumatologic disease doesn't present)
    • Treatment:
      • Non-Pharmacologic
        • Wear mittens
        • Heating pads
        • Avoid cold
      • Pharmacologic
        • 1st Line: CCB (Nifedipine or Amlodipine) + nitro paste
        • 2nd Line: Sildenafil (often not approved for RD, but is approved for Pulmonary HTN). 
        • 3rd Line: (if severe, not resolving)
          • Admit to hospital for IV Alprostadil x72hrs + cardiac monitoring
          • Loss of fingers can occur!
    • Source:
      • Dr. Joneja's Lecture Mar 2017  (Rheumatologist in Kingston, Ontario)

    Polymyalgia Rheumatica (PMR)

    • Inflammatory condition causing pain and stiffness in the shoulders and hips.
    • Often mistaken for RA.
    • Only affects joints surrounding shoulders and hips (pelvic and shoulder girtle).
      • 50%: self-limited (months to years).
      • 50%: chronic.
    • F>M (>50yo)
    • Pathophysiology:
      • Inflammation of bursae and synovium

    Symptoms

    • Sx come on suddenly (often overnight).
    • Pain + stiffness in joints surrounding pelvic and shoulder girtle in AM or after rest.
    • Fatigue
    • Sometimes occurs with temporal arteritis --> if sx or findings of GCA --> do TA biopsy
    • Can have distal involvement (50% of patients) typically MCPs, wrists, occasionally knees (not knees/ankles)

     

    Diagnosis

    • Diagnostic Criteria

      1. Age > 50yo

      2. Pain/aching/stiffness in neck, shoulders or hips/thighs > 1mo duration

      3. ESR > 40 mm/hr

      4. Exclusion of other diagnoses with all items present to dx PMR

     

    Treatment

    • Prednisone with taper.
    • Prednisone 12.5-25mg/day titrate down to lowest dose to control sx
      • Goal: Reach 10mg/day within 4-8w,.  If symptom free--> continue taper by 1mg q4w until done.
      • Often need extremely long taper >1yr.
      • ACR recommends against >30mg/day (f need such high doses consider alternate dx)
    • Not Recommended:
      • NSAIDs alone (risks of long term use)
      • Anti-TNF alpha (no evidence)
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