Joint Pain And Swelling Common Rheumatologic Concerns ROBERT VALENTE MD CENTER OF NEBRASKA LINCOLN, NE

I have no financial disclosures or conflicts of interest to report 1/3rd of All Primary Care Visits Involve a Musculoskeletal Complaint. Do You See Patients with Joint and Muscle Aches and Pains? DO YOU ALWAYS FEEL COMFORTABLE TRIAGING THESE PATIENTS?

Common Arthritis Questions • Is it inflammatory arthritis ? • Distinguishing RA from OA • What does this + ANA mean? • Distinguishing CTD from chronic pain and fibromyalgia Case 1

DISTINGUISHING INFLAMMATORY ARTHRITIS FROM OSTEOARTHRITIS

Case 1: The Reluctant Contractor 67 yo Male Contractor • Previous hx of LBP, neck pain chronic plantar fasciitis • 2 yrs previous, pneumonia, Rx included prednisone. Joints felt wonderful. • 2+ yrs of polyarthralgia, 3 ibuprofen QID, otherwise too stiff to get out of bed • No F/C/S, no wt loss. No rash or sun sensitivity, no dry eyes, eye inflammation, pleurisy, SOB, Cough, or GI distress. No numbness, Raynauds. No hx STD, kidney stones or . No hx of cancer, recent infection. • Dad with seropositive RA • Pain score 6, AM stiff 10 min What features of the Patient History suggest inflammatory polyarthritis? A. 10 min of morning stiffness B. Hx of Back pain and plantar fasciitis? C. Trial of prednisone made everything better D. Needs 12 ibuprofen a day, or too stiff to get out of bed and dad had

DDx of Polyarticular Pain • Polyarthritis: Chronic and Acute (viral) • • Fibromyalgia • Multiple site Bursitis/Tendonitis • Hypothyroidism • Metastasis

• Depression “The evaluation of the adult with polyarticular pain” • Neuropathic pain Shmerling RH, ed Wolters Kluwer, May 2018 • Metabolic/inherited bone diseases (osteomalacia, osteogenesis imperfecta) Can you tell if a joint is swollen? Case 1 • Yes • No Physical Exam • Rapid 3 = 7.5 • Moderate OA hands, 1st and 3rd MCPS, 1st CMCs, AC joints, L knee, B PF joints, toes • Bilateral Rotator cuff dysfunction • Normal Achilles, No sausage digits • Normal L-spine motion (finger to floor distance 2 inches) • 17 swollen, 20 tender joints

Case 1

LAB AND X-RAY RESULTS

• Normal: CBC, ESR, CRP, Chemistries, urine • -RF, -CCP, - ANA • X-ray hands C/W osteoarthritis, Moderate (nodal pattern) Rheumatoid Arthritis: Radiographic Abnormalities

• Soft tissue swelling • Symmetric joint involvement • Peri-articular osteoporosis • Symmetric joint space narrowing • Marginal erosions • Deformity – Fibrous ankylosis

Question Does this 67 yo Male Contractor have inflammatory Arthritis? A. Yes B. No The Case for Inflammatory Arthritis • SX > 6 weeks • Prolonged AM stiffness • SX better with ibuprofen • + family hx of Sero+ RA • 17 Swollen joints on PE

The Case Against Inflammatory Arthritis • Patient is 67 yo, and a laborer with lots of OA • No CTD disease features • No inflammatory bowel sx • No psoriasis • No STD risks, no Gout/stone • Normal ESR, CRP • Negative ANA, RF, CCP • X-rays show osteoarthritis without erosions, Ca++, etc Does Negative RF, CCP, Normal ESR Affect Your Decision A. YES B. NO

The Key: SYNOVITIS

Rheumatoid Arthritis Osteoarthritis Laboratory Testing to Discriminate Between RA and Non-RA in Patients With Early Arthritis

Sensitivity (%) Specificity (%) PPV (%) NPV (%)

Anti-CCP * 48 96 84 81

IgM RF * 54 91 74 81

Anti-CCP or RF 63 88 72 83 Anti-CCP and 39 98 91 78 RF

Elevated ESR had a PPV of only 17% for RA *Anti-CCP and IgM RF were determined by enzyme-linked immunosorbent assay (ELISA). CCP = cyclic citrullinated protein; PPV = positive predictive value; NPV = negative predictive value. Visser H, et al. Best Pract Res Clin Rheum. 2005;19:52–72.

II.14

Early Undifferentiated Polyarthritis: What Matters? Synovitis (especially @ 3 Mo) % Patients Receiving DMARDs at 12 Months

Characteristics at Baseline RF + ↑ CRP ↑ CRP RF + RF - SE + RF + Synovitis 70 43 Synovitis 60 Synovitis 62 80 No No No 40 15 0 033 synovitis synovitis synovitis

Characteristics at Month 3 RF + ↑ CRP ↑ CRP RF + RF - SE + RF + Synovitis 75 70 Synovitis 60 Synovitis 69 100 No No No 02 0 00 synovitis synovitis synovitis What Trumps What?

SE = possession of ≥ 1 allele of shared epitope (HLA-DR1,4,10); UPA = undifferentiated polyarthropathy.  CRP = C-reactive protein level ≥ 10 mg/L. SYNOVITIS ! Quinn MA, et al. Arthritis Rheum. 2003;48:3039–3045. 2010 ACR/EULAR RA Classification Criteria ≥ 6 points = RA • 1 med or large joint swelling = 0 points • 2 – 10 med or large joints swollen = 1 point • 1 – 3 small joints swollen = 2 points • 4 – 10 small joints swollen = 3 points • > 10 small joints swollen = 4 points • -RF, -CCP = 0 points • + RF or + CCP (low titer 2-3 x normal) = 2 points • +RF or + CCP high titer = 3 points • Duration of synovitis > 6 weeks = 1 point • Abnormal CRP or ESR = 1 point A & R, Aug 2010

Case 1: Dx = Seronegative RA

• Treatment Goals • Make the patient feel as normal as possible • Prevent bony damage/disability • Avoid toxicity • Cost effectiveness • Use standardized scoring to measure RA disease activity • Treat to Target (low disease activity)

2015 ACR Guideline for the Treatment of Rheumatoid Arthritis, Arthritis Rheumatol. 2016 Jan;68(1):1-26 Nell, VPK et al. al. et VPK Nell, (median of 12 months). All patients were naive to treatment with DMARDs. LERA = onset; of symptommo patients presentedwithin 3 = VERA Impact of DMARD Therapy on ACR Response Rates ACR Response Therapy on of DMARD Impact LateEarlyRA(LERA) vs Very EarlyRA(VERA) * Opportunity Window of P < 0.05 for LERA LERA VERA. 0.05 for vs < % of Patients Severity (arbitrary units) Early? Why DoWeNeedToDx The ProgressionofRA- 10 20 30 40 50 60 70 80 0 0 Rheumatology C-0AR5 C-0AR2 C-0ACR-70 ACR-50 ACR-20 ACR-70 ACR-50 ACR-20 65 ots36 months 3 months al nemdaeLate Early Intermediate 20 * . 2004;43:906–914. 51015202530 50 15 * Duration ofDisease(years) 35 Photo: Copyright © American College of Rheumatology.of College American Photo: Copyright © JR. Kirwan from Graph: Adapted * 0 patients presented between 9 months and 3.5 years after 3.5 yearsafter symptomand presented between 9 monthspatients 70 40 60 * 25 J Rheumatol. Rheumatol. J 55 * Joint Damage Disability Inflammation 20 LERA patients VERA patients 2001;28:881–886. onset II.22 Case1: Treatment • Problems with dysphagia • Initially did not use / continue NSAID • Upper endoscopy negative This Photo by Unknown Author is • Started back on Ibuprofen 600 mg TID licensed under CC BY-NC-ND • Prednisone 5 mg Q AM (with taper beginning at 8 wks • Methotrexate, increasing dose to 20 mg po Q week • Folic acid • @ 2 mo Rapid 3 was 4, down from 7.5, AM stiff 15 min • Swollen joint count 11, down from 17

Case 2

WHEN DOES A POSITIVE ANA MEAN SOMETHING?? WHEN TO AVOID CHECKING AN ANA! Case 2: The Stiff Daycare Provider • 23-year-old nonsmoking female daycare provider • Onset of pain and stiffness and swelling in her hands and wrists beginning February 2017. Compromised activities of daily living. • Morning stiffness that would last up to 4 hours • Primary care evaluation documented new onset hypothyroidism. No improvement in joint symptoms with T4 • Trial of prednisone with prompt but temporary benefit. Minimal benefit with diclofenac • Mother notices puffy fingers • At the same time, patient’s develops classic white attacks/Raynaud’s phenomenon. No other formal CTD sx. (No SOB, swallowing difficulty, Dry eyes, oral ulcers, numbness, rash)

What historical features suggest inflammatory arthritis? A. Pain and stiffness in the hands B. Prednisone helped temporarily, diclofenac without benefit C. Puffy, swollen fingers noted by mom D. Raynaud’s phenomenon E. New onset hypothyroidism F. All of the above Fibromyalgia • Muscle attachment pain • Hurt all over (Large > small joints) • All day stiffness • No swollen joints • Normal inflammatory markers • Other complaints • Fatigue, cognitive problems, • Paresthesia, headache • Irritable bowel and bladder +ANA ≠ inflammatory arthritis

Predicting Pain in OA pts after TKA and THA Fibromyalgia-ness (FM-ness) Calculated with the • Outcomes Polysymptomatic Distress Scale • Post op opioid consumption • Pain relief @ 6mo • 9 mg > Morphine requirements for each point higher “FM-ness” • 20% less likely to reach 50% less pain after arthroplasty with each point higher “FM-ness” Brummett, etal. Anesthesiology, 2013 DDx of Polyarticular Pain • Polyarthritis: Chronic and Acute (viral) • Reactive arthritis • Fibromyalgia • Multiple site Bursitis/Tendonitis BUT… • Hypothyroidism • Metastasis

• Depression “The evaluation of the adult with polyarticular pain” • Neuropathic pain Shmerling RH, ed Wolters Kluwer, May 2018 • Metabolic/inherited bone diseases (osteomalacia, osteogenesis imperfecta)

This is Polyarthralgia/itis + Something ELSE

FORMAL CTD / SLE SPONDY / IBD/ VASCULITIS HEPATITIS PSORIATIC • Polyarthritis + • Polyarthritis + • Raynauds • Polyarthritis + • Inflammatory back • New HA, visual changes • Polyserositis pain • Claudication • Rash • Iritis • Nephritis • Sun sensitivity • Psoriasis • • Dry Eyes • Inflammatory Bowel Pulmonary infiltrates • Multiple Miscarriages disease • Pulmonary hemorrhage • DVT • Hx of dysentery or • Neuropathy STD • Seizures • Purpura / ulcers • Renal disease • Cytopenias Case 2: Physical Exam • Wt 134#, BP 96/65, Pain 8.5 • Skin: puffy fingers +++ nailfold capillary changes - telangiectasia, scleroderma -psoriasis, Nodules • CV: no murmur, 4+ pulses, - Allen’s test bilaterally • Lungs, Abd, Neuro, Extremities all normal. No edema • Raynaud’s phenomenon • 18 swollen and tender joints

Case 2: Lab and X-ray • Lab from home • Normal ESR, CRP, TSH, Lyme titer, B12, Vit D 26.8 • CXR normal • Lab after Rheum Visit • Hand x-ray normal except • Normal Hepatitis profile B,C for soft tissue swelling • Normal CBC, SPEP Chemistries (Cr, AST, CPK), urinalysis • -ANA, ++++RF, complement Case 2: Does this patient have A. Fibromyalgia? B. Rheumatoid Arthritis ? C. Thyroid myxedema ? D. Myositis sine Myositis? E. Scleroderma?

Additional Studies • + PM/ScL, + RNA pol III, - ENA (ACA, Scl-70, RNP), - anti- myositis Abys • Echo normal • PFTs: FVC 65, FEV1 64 DLCO 57, TLC 60 (Restrictive Lung Disease) She has Scleroderma / systemic sclerosis • Scleroderma • Inflammatory polyarthritis • Raynaud’s phenomenon • Nailfold capillary changes • + RNA Polymerase III • + PM/ScL • +RF • Restrictive lung disease

Systemic Sclerosis (SSc)

Subsets of SSc are : • 70% of Systemic Sclerosis can be • Diffuse cutaneous SSc (dcSSc) serologically defined.

• Limited cutaneous SSc (lcSSc) CREST • Serologic markers can separate Diffuse systemic sclerosis (+Scl-70) • SSc sine scleroderma, in which from limited /CREST(+Centromere) patients have only internal organ involvement • + RNA pol III • Environmentally-induced scleroderma puffy fingers, contracture, high risk of scleroderma renal crisis, 1st 5 • Overlap syndromes, in which features years heightened risk of interstitial of SSc coexist with elements of other lung disease, increased risk of rheumatic disorder cancer

“Overview and classification of scleroderma disorders”, Denton, CP, ed Wolters Kluwer, November 2016 Scleroderma Mortality

Czirjak, etal, Survival and cause of death in 366 Hungarian patients with Systemic Sclerosis. Ann Rheum Diseases 2008, 67:59-63

Systemic Sclerosis Treatment

• Arthritis and puffy fingers • Raynaud's /scleroderma • nifedipine, amlodipine, • Methotrexate, Hydroxychloroquine, (dihydropyridines),phosphodiesterase- Mycophenolate, 5 inhibitors, topical nitrate, fluoxetine, gabapentin, pregabalin Botox, sympathectomy, endothelin • Avoid prednisone > 5 mg/day receptor antagonists, prostacyclin, clopidogrel • Interstitial lung disease • Corticosteroids (short term) • Pulmonary Hypertension • Anticoagulation, endothelin receptor • Mycophenolate, Cyclophosphamide antagonists, phosphodiesterase-5 • Autologous bone marrow transplant inhibitors, prostacyclin (IV and oral) • Renal • Esophageal dysmotility, esophagitis and stricture, • ACE inhibitors, … bacterial overgrowth • (symptomatic , antibiotics-Rifaximin) Case 2 • Hydroxychloroquine • PFTs stabilized after 9 mo • Mycophenolate • BPs normal • Prednisone 5 mg • 14 swollen joints • Pregabalin • 30 min AM stiff, Pain score 7 • Omeprazole • No pulmonary HTN as of now • IUD (not BCPs)

Summary • Does the patient have Inflammatory Arthritis? Is there synovitis on examination? • Does the patient have a CTD / ? Is there synovitis? Is there something else? Rash, renal disease, serositis, Raynaud's, Severe dry eyes, cytopenia's Team Valente