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Describe common rheumatologic diseases Identification • Kristine M. Lohr, MD, MS and Treatment • Professor of Medicine and Chief of Determine routine diagnostic of Rheumatology Division Objectives evaluations for rheumatologic • University of Kentucky College of Medicine diseases prior to referral Rheumatologic • April 20, 2021 Diseases Describe new treatment modalities and alternative therapies for rheumatologic diseases

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Prevalence Rates of Common Rheumatic Diseases

• Osteoarthritis • Rheumatoid arthritis Most common • Gout rheumatologic • diseases • Fibromyalgia • Psoriatic arthritis • Ankylosing spondylitis

Centers for Disease Control and Prevention March 2017 Vital Signs

https://nccd.cdc.gov/cdi/rdPage.aspx?rdReport=DPH_CDI.ExploreByTopic&islTopic=ART&islYear=9999&go=GO 3 4

Arthritis among Adults Aged >18 yr. in Kentucky Age-adjusted Prevalence (%) Rheumatic Joint Disorders: History

Male Female Survey Year Inflammatory Non-inflammatory (Mechanical) All adults aged > 18 yr. 27.8 33.3 2018 Joint pain In the AM, at rest, & with use With use, improved with rest With obesity 32.9 40.0 2018 Stiffness Prolonged morning (>1 hr.) Short-lived after inactivity With diabetes 64.7 40.6 2018 Fatigue Significant Minimal With heart disease 47.2 53.9 2018 Activity May improve stiffness May worsen symptoms Activity limitation due to doctor-diagnosed arthritis 49.5 64.0 2015 Rest May cause gelling May improve symptoms Severe joint pain due to doctor-diagnosed arthritis 35.3 38.3 2017 Instability Buckling, give-way Work limitation due to doctor-diagnosed arthritis 57.2 57.7 2017 Systemic involvement Yes No Physical inactivity 36.2 39.0 2018 Corticosteroid responsiveness Yes No

CDC Behavioral Risk Factor Surveillance System (health survey)

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Rheumatic Joint Disorders: Exam Findings Rheumatic Joint Disorders: Exam Findings

Feature Rheumatoid Arthritis Osteoarthritis (Mechanical) Rheumatoid arthritis Osteoarthritis (Mechanical) Joint involvement Almost any Predominantly weight-bearing joints & Symmetry Yes Occasional hands, mid-cervical, mid-lumbar Synovitis Yes Rarely (may occur in erosive OA) Swelling Distended joint capsule Bony (“stony”) hypertrophy • Distal interphalangeal No Heberden nodes Firm, rubbery Irregular • Proximal interphalangeal Yes Bouchard nodes Spindle-shaped Nodular • Thumb carpometacarpal No Yes • Wrist Yes No Crepitus None or fine Rough Deformities Swan neck DIP or PIP angulation Range of motion Limited Limited Boutonniere Nodules (subcutaneous) Yes No Subluxation Extraarticular signs Yes No Ulnar drift

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• Most generalized rheumatic disorders • E.g., rheumatoid arthritis, systemic lupus erythematosus • Weight loss • Fibromyalgia • Fever • Poor sleep Contributors • Color changes (e.g., black, dark purple) or • Related to pain coldness of digits or limbs to Fatigue & • Poor-quality Red Flags • Temple headache, pain with scalp Malaise • Heartburn, nocturia, CHF, neurologic tenderness, visual disturbance disorders, hyperthyroidism, OSA • • Medications, alcohol, caffeine Loss of sensation or motor function • • Depression & other mental health problems Difficulties with urination or defecation

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• CBC • Lymphopenia in active SLE or with Acute Phase Reactants immunosuppressive drug treatment • Thrombocytosis (inflammation) or Elevated Westergren ESR Elevated C-reactive Protein Screening tests thrombocytopenia (active SLE) • Infection • Infection • Anemia (inflammation/chronic disease) • Rheumatic disease • Rheumatic disease prior to • Renal function & urinalysis • Higher in women • Higher in women • rheumatologic Aminotransferases • Increased with age • Increased with age referral • Serum uric acid • Obesity • Obesity • • Metabolic stress, e.g., insulin Acute-phase reactants • Malignancy • ESR (higher in women; increased with resistance age) • Renal disease • Race • CRP (higher in obese patients) • Anemia • Tissue injury/ischemia

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• High specificity & moderate sensitivity for RA • Can be present up to a decade before clinical • Hepatitis C & B, bacterial endocarditis, TB, Autoantibodies: disease chronic bronchitis Anti- • Can be positive in Autoantibodies: • 5-6% of older adults in normal population • ~25% of RF-negative RA citrullinated Rheumatoid • Specificity increases with higher titer • With erosive disease in SLE, primary Sjogren, Peptide psoriatic arthritis Factor • Suspicion of RA or Sjogren syndrome • Active TB • 20-30% of RA patients are Antibodies • Rare in hepatitis C seronegative (ACPAs) or CCP • Rare in alpha-1 antitrypsin deficiency and in COPD

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Autoimmune Disease Sensitivity (%) Systemic lupus erythematosus 95-100 ANA 1:40: 20-30% Systemic sclerosis 60-80 Mixed connective tissue disease 100 Poly/dermatomyositis 60 ANA 1:80: 10-15% Rheumatoid arthritis 50 Autoantibodies: Can a positive Rheumatoid vasculitis 30-50 Anti-nuclear Sjogren syndrome 40-70 ANA occur in ANA 1:160: 5% Antibodies Drug-induced lupus 15 a normal Pauciarticular juvenile idiopathic 70 (ANAs) arthritis healthy ANA 1:320: 3% Nonrheumatic Disease Sensitivity (%) Frequency of

Hashimoto thyroiditis 45 ANAs person? Healthy relative of an SLE patient: 5-25% (usually low titer) Graves disease 50 Autoimmune hepatitis 50 Primary pulmonary hypertension 40 Age >70 years: up to 70% positive at ANA titer 1:40

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Rheumatoid Arthritis: Pharmacologic Therapy

Conventional DMARDS Biologic DMARDs Targeted Synthetic DMARDs • Methotrexate TNF-alpha inhibitors inhibitors • Leflunomide • • • Sulfasalazine • • • Hydroxychloroquine • • • • IL-6 receptor antagonist • • T-cell costimulation blocker • Abatacept (CTLA4-Ig) Anti-CD20 B-cell depleting • Rituximab

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Management of Osteoarthritis: Management of Osteoarthritis Recommended Physical, Psychosocial & Mind-Body Approaches Recommended Pharmacologic Approaches

Modality Hand Knee Hip Drug Hand Knee Hip Exercise Strong Strong Strong Oral NSAIDs Strong Strong Strong Self-efficacy & Self- Strong Strong Topical NSAIDs Conditional Strong Management Programs Intra-articular Steroids Conditional Strong Strong (imaging-guidance) Weight loss, Tai Chi, Cane Strong Strong Acetaminophen Conditional Conditional Conditional st Assistive device Strong: 1 CMC Orthosis Strong: Tibiofemoral Knee Brace Tramadol Conditional Conditional Conditional Duloxetine Conditional Conditional Conditional Conditional: Heat, therapeutic cooling, cognitive behavioral therapy, acupuncture, kinesiotaping, balance training, other hand orthoses, patellofemoral knee brace, paraffin, yoga, radiofrequency ablation Chondroitin Conditional Topical capsaicin Conditional

Kolasinski SL et al: 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Kolasinski SL et al: 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care Res 2020 Feb;72(2):149-62. of the Hand, Hip, and Knee. Arthritis Care Res 2020 Feb;72(2):149-62.

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• The epitome of a red, hot, swollen joint • But acute monoarthritis = infection Triggers of acute gout till proven otherwise! • Rare in men aged < 25 years & in • Alcohol ingestion • Trauma Acute premenopausal women • Initiation of urate-lowering therapy • Radiation or chemotherapy Monoarthritis: • Diagnosis: tap the joint • • • Needle-shaped negatively Dietary excess of purines Fructose ingestion Gout birefringent crystals + leukocytes • Acute medical illness (e.g., infection) • Postoperative days 3-5 (20,000-100,000/cu mm) • Exercise • Dehydration • Serum uric acid can be normal during • Drugs an attack

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Drugs that decrease renal excretion of urate

Drugs that • Amlodipine • Cyclosporine • Ethambutol • Atorvastatin • Alcohol • Low dose ASA mildly • Fenofibrate • Nicotinic acid • Pyrazinamide increase renal • Leflunomide • Thiazides • Levodopa • Losartan • Tacrolimus • Theophylline excretion of • Rosuvastatin • Furosemide & loop diuretics • Didanosine urate • High-dose salicylates

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• Moderate intake of purine-rich food • Asparagus, cauliflower, spinach, mushrooms • Typically decreases serum uric acid by <1 mg/dL • Nuts • Weight loss • Legumes (beans, peas, lentils) Can diet & • Can diet & Complex carbs (fruits, vegetables, whole grains) • Proteins: lifestyle alone • Hydrate with water lifestyle alone • Lean meat & poultry • Limit • Low-fat dairy (milk, yogurt) manage • Saturated fats (red & organ meats, fatty poultry, manage • May reduce risk of gout high-fat dairy products) • Coffee in moderation, especially regular caffeinated symptomatic • symptomatic Seafood (shellfish, sardines, anchovies) • Vitamin C 500 mg/day • gout? Fructose (soda, fruit juice, energy drinks) gout? • Tart cherries • Moderate consumption of wine

https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in-depth/gout-diet/art-20048524 https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in-depth/gout-diet/art-20048524

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Treatment of Acute Gout

Options Dosage Comments NSAIDs Indomethacin 50 mg po qid 24-48 hr., then Contraindicated in moderate/severe CKD • Frequent attacks (>2-3 over 1-yr. period) TID x 48 hr., taper off after attack subsides NSAIDs w/ short half-lives OK When do you Oral colchicine 1.2 mg po followed by 0.6 mg po 1 hr. later Within 36 hr. of onset initiate urate- • Renal stones (urate or calcium) Avoid in elderly, renal or hepatic insufficiency, use with • Tophaceous gout (on exam or x-ray) concomitant P450 & P-glycoprotein inhibitors* Intra-articular 40 mg for large joints, 10-20 mg for small 1-2 involved joints or bursae lowering • Moderate-to-severe CKD corticosteroids joints or bursae Within 24 hr. of attack • Congestive heart failure (on diuretics) Oral Prednisone 0.5 mg/kg qd x 5-10 days, then May be used in patients with CKD therapy? corticosteroids taper 7-10 days Rebound arthropathy may occur Triamcinolone acetonide 60 mg IM

*Cyclosporine, clarithromycin/erythromycin, keto- & itraconazole, disulfiram, HIV protease inhibitors, diltiazem, verapamil, grapefruit juice

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How to initiate urate-lowering therapy How to initiate urate-lowering therapy

• Prophylaxis for first 3-6 mo. • Xanthine oxidase inhibitors • Oral colchicine 0.6 mg qd or BID (less in elderly patients, CKD) • Allopurinol 100 mg qd (less if CKD), gradual taper up (often >300 • NSAIDs mg qd, max 800) • Low-dose glucocorticoid (e.g., prednisone 5-10 mg/day) • Febuxostat 40 mg qd, titrate to 80 mg to reach goal • DO NOT STOP OR REDUCE DURING A FLARE!!!! • Screen HLA-B*5801 if Korean, Han Chinese or Thai descent; consider African Americans w/ CKD3 or worse • Start urate-lowering therapy low & slow • Uricosuric • Goal = SUA <6.0 mg/dL, or <5 mg/dL if tophi • Probenecid (contraindicated in overproducers, GFR <50 mL/min) • Check serum uric acid every 2-3 wk. till goal reached • Pegloticase (recombinant pegylated uricase) IV @ 2-wk intervals

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Systemic Lupus Erythematosus: • Sun protection Signs & Symptoms • Balanced diet (carbs, proteins, fats) • Monitor 25-hydroxyvitamin D • Constitutional: Fatigue, fever, weight loss Systemic Lupus • Exercise • Arthritis or arthralgia Erythematosus: • Smoking cessation • Skin: butterfly rash, photosensitivity, alopecia, Raynaud phenomenon, purpura, urticaria Nonpharmacologic • Renal: nephritis • Immunizations (Safe: flu, pneumococcal, HPV, & Preventive hepatitis B) • Gastrointestinal: mucous membrane lesion, esophageal, hepatomegaly, peritonitis • Pulmonary: pleurisy, effusion, interstitial lung disease Interventions • Treat comorbid conditions (atherosclerosis, PHT, antiphospholipid syndrome, osteopenia/ • Cardiac: pericarditis, myocardial dysfunction, microvascular angina osteoporosis • Hematologic: splenomegaly, lymphadenopathy, cytopenias • Avoid sulfonamide-containing antibiotics • Neuropsychiatric: headache, psychiatric, cognitive, CVA, seizures

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Systemic Lupus Erythematosus: Pharmacologic Interventions SLE: Newer Pharmacologic Agents

Mild: Add NSAIDs &/or short- Hydroxychloroquine (HCQ) or term low-dose prednisone < 7.5 • Human monoclonal antibody inhibits soluble B-cell chloroquine mg qd survival factor (BLyS or BAFF) • Active musculoskeletal or cutaneous disease (IV or SQ) unresponsive to standard therapy

Anifrolumab • Monoclonal antibody against type I receptor Severe (life threatening): high- (January 2020) • Phase III trial (N=362): improved clinical response Moderate (non-organ dose pulse methylprednisolone rates, steroid requirements, skin disease severity threatening): HCQ + short-term 0.5-1 g/day x 3 days or 1-2 • Adverse effects: herpes zoster, bronchitis low-dose prednisone < 5-15 mg mg/kg/day, followed by Still in trials qd, azathioprine, methotrexate mycophenolate, azathioprine, cyclophosphamide, rituximab

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Fibromyalgia: Central Pain Disorder Allodynia Diffuse Hyperalgesia • Chronic widespread body pain & tenderness • Problem with pain “volume control” • Hypersensitive to sensory stimuli • FATIGUE • Cognitive: trouble concentrating, forgetful, disorganized thinking • Sleep & mood difficulties • Stiffness, muscle & joint pain • Subjective joint swelling • Numbness, tingling, burning, creeping or crawling sensations (esp. arms & legs) • Pain & fatigue worse with minor activities & prolonged inactivity

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Evaluation in Chronic Widespread Pain Fibromyalgia: Treatment Goals Careful & complete H&P Pain control (reduction), not pain elimination Check ESR, CRP, CBC, chemistry panel, TSH Live a normal / fulfilling life despite pain Maintain function AVOID ANA & RF!!!! Maintain control over symptoms

“When you eliminate 90% of a patient’s pain, the remaining 10% is 100% of Normal w/u Abnormal w/u what is left.” Educate Manage comorbidities -Leslie Crofford, MD Reaffirm fibromyalgia is a Consider comorbid fibromyalgia benign condition

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Fibromyalgia: Coping with Chronic Pain Non-Pharmacologic & Modifiable Factors • Progressive muscle relaxation (e.g., guided meditation) • Education/reassurance • Response to stress/reversible • Controlled breathing techniques stressors • Physical activity/aerobic exercise • Biofeedback • Sleep hygiene • Maladaptive attitudes towards pain, e.g., helplessness & catastrophizing • Imagery • Psychiatric care (anxiety, depression/mood) • Poor job or life satisfaction • Tai chi, yoga • Cognitive behavioral therapy • Obesity • *Cognitive behavioral therapy • Alternative therapies • *Exercise (aerobic; low impact)

Establish realistic expectations!

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EULAR Revised Recommendations: Management of Fibromyalgia http://fibroguide.med.umich.edu/ Recommendation Level of Grade Strength of Agreement Evidence Agreement (%) 10 Modules & Worksheets Overarching Principles  Optimal management requires prompt diagnosis & assessment of pain, function IV D 100 • Understanding FM & psychosocial context  Management should aim at improving HRQoL balancing benefit & risk of IV D 100 • Setting Goals treatment. Initial management should focus on non-pharmacologic treatment • Communicating Specific recommendations  Non-pharmacologic management • Thinking Differently  Aerobic & strengthening exercise 1a A Strong for 100 • Being Active  Cognitive behavioral therapies 1a A Weak for 100  Multicomponent therapies 1a A Weak for 93 • Sleep  Defined physical therapies: acupuncture or hydrotherapy 1a A Weak for 93  Meditative movement therapies (qigong, yoga, tai chi) & mindfulness- 1a A Weak for 71-73 • Relaxation based stress reduction •  Pharmacologic management Pacing  Amitriptyline (at low dose) 1a A Weak for 100 • Time for You  Duloxetine or milnacipran 1a A Weak for 100  Tramadol 1a A Weak for 100 • FibroFog  Pregabalin 1a A Weak for 94  Cyclobenzaprine 1a A Weak for 75 ACR Patient Handout: https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Fibromyalgia Macfarlane et al. Annals of Rheumatic Disease 76:318,2017 41 42

7 4/2/2021

Describe common rheumatologic diseases

Determine routine diagnostic Objectives evaluations for rheumatologic diseases prior to referral

Describe new treatment modalities and alternative therapies for rheumatologic diseases

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2019 EULAR/ACR Aringer M et al. Arthritis Rheumatol. Classification • Aringer M et al. Arthritis Rheumatol. 2019 Sep;71(9):1400-1412. doi: 2019 Sep;71(9):1400-1412. doi: 10.1002/art.40930. Epub 2019 Aug 6. 10.1002/art.40930. Epub 2019 Aug 6. Criteria for SLE

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Physical, Psychosocial & Mind-Body Approaches Pharmacologic Approaches for Management of OA for Management of Osteoarthritis Strongly Against Conditionally Against Hand, hip & knee Hand, hip & knee • • Bisphosphonates • Colchicine Strongly against • Glucosamine • Non-tramadol opioids • TENS • Hydroxychloroquine • Fish oi • Methotrexate • Vitamin D • Conditionally against • TNF inhibitors • Iontophoresis • IL-1 receptor antagonists • Manual therapy + exercise Hip & knee Hand • Platelet-rich plasma • Chondroitin • Massage therapy • Stem cell injection • Topical capsaicin • Modified shoes • Chondroitin • Wedged insoles Hip Hand & knee • Intra-articular hyaluronic acid • Intra-articular hyaluronic acid • Pulsed vibration therapy Knee & hip • Intra-articular botulinum toxin • Prolotherapy Kolasinski SL et al: 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care Res 2020 Feb;72(2):149-62. Kolasinski SL et al: 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis Care Res 2020 Feb;72(2):149-62. 47 48

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Educational Resources for Fibromyalgia

• ACR Patient Handout: • https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases- Conditions/Fibromyalgia

• National Institute for Arthritis and Musculoskeletal and Skin Disorders • National Fibromyalgia Association • National Fibromyalgia and Chronic Pain Association • National Fibromyalgia Partnership, Inc. • The American Fibromyalgia Syndrome Association, Inc.

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