Approach to Joint pain Prepared by Foad Ahmadi, MD, MPH Supervised & edited by Dr. Bindu Swaroop Dr. Sheetal Desai [pending] Dr. George Lawry [pending]

Let’s start with case #1: Approach to Joint Pain Objectives To characterize / describe join pain(s) using proper terminology To take a systematic approach to diagnose the cause of joint pain(s) Let’s start with case #1: A 60 yo female presents with 3 months of gradually worsening joint pains on her wrists, MCPs, PIPs, ankles, and MTPs. The pain is worse in the morning, is associated with stiffness on her joints, and both pain and stiffness improve after about 1 hour of physical activity. On PEx, you notice swelling and warmth on the abovementioned joints as well as tenderness on both active and passive range of motion (ROM). Now, how can we describe her symptoms in just a few words? Answer: Chronic symmetric polyarthritis (of small joints). That’s it! How did we do it? Let’s take a look…

Step 1: Characterize join pain(s)! Approach to Joint Pain Step 1: Characterize join pain(s)! 1a. What’s the chronicity of joint pain(s)? Acute: hours to days Chronic: weeks to months 1b. Does the pain seem inflammatory or non-inflammatory? Inflammatory pain (“itis”): Swelling, warmth, redness, Typically worse in the morning, >30 min morning stiffness, improvement with motion/exercise Non-inflammatory pain (“algia”): Just the opposite: No morning stiffness or pain, Pain is triggered by physical activity & is worse towards the end of the day 1c. What’s the distribution of the involved joints? Mono: 1 joint Oligo: 2-4 joints Poly: ≥5 joints if poly: symmetric or asymmetric? 1d. Does the pain sound articular or periarticular? Articular pain: Pain on both active & passive ROM Periarticular pain: Pain on active ROM >> passive ROM

Back to our case #1 Let’s throw in case #2  Approach to Joint Pain In our 60 yo lady with chronic symmetric polyarthritis (of small joints), what is the most likely etiology? Let’s throw in case #2  75 yo male presents with 2 months of gradually-worsening stiffness and pain on her shoulders and hips. Her symptoms are worse in the morning, and they improve after about 2-hours of moving and physical activity. On PEx, she has stiffness and pain with active ROM on her shoulders, hips, and knees; however, she has no more than minimal pain with passive ROM. A) let’s characterize her joint pains! B) what is the most likely etiology? Answer for case #1: Most likely cause is rheumatoid arthritis (RA) Answer for case #2: She has chronic symmetric proximal periarthritis, and the most likely cause is polymyalgia rheumatica (PMR). How did we guess? Let’s take a look…

Step 2: Pick your DDx (1/2) Articular pain Approach to Joint Pain Characteristics DDx Acute Non-inflammatory Mono-arthralgia Trauma / Fracture / Hemarthrosis / Soft-tissue injury Osteonecrosis (e.g. d/t steroids, sickle cell) Acute Inflammatory Mono/Oligo-arthritis Septic arthritis (typically monoarthritis except if hematogenously spread) Crystal-induced arthropathies (gout / CPPD) Reactive arthritis Acute Inflammatory Poly-arthritis Viral arthritis (e.g. HBV, HCV, acute HIV, Parvovirus B19) Early chronic inflammatory polyarthritis (see below) Chronic Non-inflammatory arthralgias (Mono/Oligo/Poly) Osteoarthritis (DJD) Chronic Inflammatory Mono/Oligo-arthritis Spondyloarthropathritis (typically causes oligoarhtritis) Indolent infections (e.g. TB, cocci, histo) Lyme (causes migratory mono/oligoarthritis) Chronic Inflammatory Poly-arthritis Rheumatoid arthritis Connective tissue diseases (e.g. SLE) Chronic CPPD inflammatory arthritis (pseudo-RA) If asymmetric: Psoriatic arthritis (can also be oligo) Articular pain Why RA is most likely? b/c A) it’s the most common cause of chronic inflammatory polyarthritis; and B) the pattern of her joint involvements (wrists, MCPs, PIPs but not DIPs, and not knees) is consistent with RA. Spondyloarthropathies: ankylosing spondylitis (AS), psoriatic arthritis, IBD-associated arthritis, reactive arthritis. Our lady’s Dx is here (This table only contains common etiologies) [ Note that “–algia” means non-inflammatory, and “–itis” mean inflammatory; so we can drop the inflammatory / non-inflammatory part! The only exception is osteoarthritis (OA), which is not a true inflammatory process (even though there is mild chronic inflammation in OA ]

Step 2: Pick your DDx (2/2) Periarticular pain Approach to Joint Pain Characteristics DDx Acute Non-inflammatory Mono-periarthralgia Tendon / Ligament injury Acute Inflammatory Mono-periarthritis Tendinitis / Bursitis Acute Non-inflammatory Poly-periarthralgias Viral arthralgias (≠ viral arthritis) Acute, Inflammatory, Poly-periarthritis Disseminated gonococcal infection (DGI) Chronic Non-inflammatory Mono-periarthralgia Unhealed chronic bone / soft tissue injury Chronic Inflammatory Mono-periarthritis Osteomyelitis close to joint Tenosynovitis (non-infectious) Malignancy around joint (e.g. metastases) Chronic Non-inflammatory Poly-periarthralgias Metabolic bone disease Hypothyroidism Polymyalgia rheumatica (PMR) Sarcoid arthropathy Periarticular pain Our guy’s Dx is here (This table only contains common etiologies) [ Again, we can drop the inflammatory / non-inflammatory part as ”–algia” means non-inflammatory, and “–itis” mean inflammatory! ]

Now I’m throwing in case #3 Approach to Joint Pain Back to case #1 Now, for our 60 yo lady with chronic symmetric polyarthritis, what should we test to diagnose her condition and rule out other likely DDx? Now I’m throwing in case #3 A 25 yo previously-healthy male presents with rapidly worsening severe pain and swelling on his Rt knee as well as tactile fevers and chills since last night. 3 days ago, he bumped into a tree when biking, which caused a small wound on his Rt knee. On PEx, he has marked swelling, redness, and warmth on his right knee, as well as severe tenderness on both active and passive ROM. What should we test to diagnose the cause of the acute monoarthritis of his Rt knee? Answer for case #1: It is appropriate to test ESR, CRP, RF, anti-CCP, and ANA. Answer for case #3: Let’s do an arthrocentesis – quickly – as he likely has septic arthritis! Why for case #1 we didn’t test ds-DNA, SSA/SSB, and other cool auto-Abs? b/c except RF and anti-CCP, the other connective tissue disease-related auto-Abs are subtypes of ANA. Thus, a negative ANA automatically means negative ds-DNA, Smith, SSA/SSB/ Scl-70, centromere, U1-RNP, etc! Why for case #3 we didn’t do imaging e.g. X-ray or MRI? b/c we are not concerned about bone of soft-tissue injury. If it was a fracture or a soft-tissue injury, the pain would start right after the injury, not after 2 days. For case #1, why we didn’t test ds-DNA, SSA/SSB, and other cool auto-Abs? For case #3, we we didn’t start with an imaging?

Step 3: Pick your diagnostic tests! Approach to Joint Pain Step 3: Pick your diagnostic tests! Tips: Choose your tests wisely (don’ order every auto-Ab on the planet!) Rule out emergencies (esp. septic arthritis) & test for the most likely DDx Associated systemic sxs increase the likelihood of systemic diseases Here are some rules of thumb: If suspected this DDx… Do these test(s)… Septic or crystal-induced arthritis Arthrocentesis Chronic polyarthritis with systemic sxs ESR, CRP, RF, anti-CCP, ANA Osteoarthritis X-rays Of course this slide is too small to include the pertinent diagnostic tests for all causes of joint pain!

Step 4: Interpret test results like a pro! Approach to Joint Pain Step 4: Interpret test results like a pro! Use “Bayes Theorem” principle (test results alone don’t dictate our diagnosis): Pre-test information + Test results  Post-test information Example: A 100 yo white male presents with chronic arthralgias on his hips, knee, ankles, and feet, aggravated by physical activity and alleviated by rest. He has no systemic sxs. ANA ordered by ED comes back positive; is it SLE? NO! b/c prior to testing, we already knew SLE was unlikely (and ANA should not have been tested) 2nd Example: A 65 yo female with family Hx of RA in her mother and sister, undoctored for many years, presents with >5 years of of symmetric polyarthritis on her wrists, MCPs, and PIPs; marked ulnar deviation; and multiple swan-neck deformities. ESR and CRP are markedly elevated, however RF and anti-CCP are both negative. What is it? Despite negative RF and anti-CCP, it is still RA (seronegative RA)! Why? b/c prior to testing, our likelihood for RA was very high to the point that even negative RF and anti-CCP do not rule it out. [ Kids, I’m sorry if things are not very straightforward in rheumatology! That’s the beauty of it  ]

Back to case #3: You haven’t had enough cases? here we go: Case #4: Approach to Joint Pain Back to case #3: We just did arthrocentesis on our young guy with possible septic arthritis; What would we expect to see on her join fluid analysis? You haven’t had enough cases? here we go: Case #4: A 35 yo African-American lady with SLE is transferring her care to us. She brings her prior records, which includes a complete panel of auto-Abs. Which auto-Abs is almost certainly ⊕? Which other auto-Abs may be ⊕? Answer for case #3: We expect to see opaque fluid with >50k WBCs & >75% PMNs. Answer for case #4: ANA is almost always ⊕ in SLE; also ds-DNA and Smith may be ⊕, in which case we have strong lab evidence of SLE (as they’re very specific for SLE). Other non-specific autoantibodies e.g. SSA/SSB or RF may be ⊕ as well. Now let’s get more comfortable with joint fluid analysis and Auto-Abs!

Joint fluid analysis Beware: Approach to Joint Pain Joint fluid analysis Normal joint Non-inflamm. (e.g. in OA) Inflammatory (e.g. in gout) Septic arthritis Appearance clear clear or yellow clear to opaque opaque WBC <200 <2000 >2000 usually >50k Polys <25% >50% >75% Culture neg Positive* Crystals (Intracellular) positive Neg+ Beware: ⊖ joint aspirate culture does not rule out septic arthritis! esp. if pt received antibiotics prior to arthrocentesis! ⊕ intracellular crystals do not rule out septic arthritis! pt can have both! Our young guy’s results are likely similar to these

Auto-antibodies Approach to Joint Pain Note that one auto-Ab can be associated with ≥1 disease; for example: RF can be positive in various connective tissue diseases (+RF doesn’t necessarily mean RA); Ro/La (SSA/SSB) are most commonly positive in Sjogren, but can be positive in up to ¼ of SLE pts! Each auto-Ab is associated with which disease(s)? We got you covered: You could use this column to guess our African-American lady’s auto-Ab results RA SLE Sjogren’s Diffuse SSc Limited SSc IM MCTD RF 70% 35% >75% 30% 15% 50% ANA 40% >95% >90% 75-95% ds-DNA ⊖ 75% rare Smith 20% Ro/La 25% 45% Scl-70 10% PNA-PIII Centromere 60% Jo-1 U1-RNP always SSc: systemic sclerosis; IM: inflammatory myositis; MCTD: Mixed connective tissue disease. The above percentages indicate sensitivities (i.e. in what percentage of each disease, that particular auto-Ab is ⊕) Ref: Connective tissue diseases. In: Pocket Medicine, 6th ed. Sabatine, MS (Ed), Lippincott Williams & Wilkins, Philadelphia, PA, 2016.

Approach to Joint Pain Summary Approach to joint pain consists of characterizing it, picking DDx, selecting pertinent diagnostic tests, and interpreting their results; The 1st step to diagnose the etiology of joint pain is to differentiate acute / chronic, inflammatory / non-inflammatory, mono- / oligo- / poly-, and articular / periarticular pain; To pick diagnostic tests, we should firstly aim to rule out emergencies and to test for the most likely etiologies; Test results should be interpreted in the light of pre-test information, not in solo!

Congratulation! You did it! Approach to Joint Pain Congratulation! You did it! Now you can kneel, then rise as “joint pain” experts  References Approach to patient with joint pain. In: Pocket Medicine, 6th ed. Sabatine, MS (Ed), Lippincott Williams & Wilkins, Philadelphia, PA, 2016. Pain and swelling of joints. In: Harrison’s manual of Medicine, 19th ed. Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J (Ed), McGraw Hill, New York NY, 2016. Joint pain. In: Pocket Emergency Medicine, 3rd ed. Zane RD, Kosowsky, JM (Ed), Lippincott Williams & Wilkins, Philadelphia, PA, 2015. Don L Goldenberg, MDDaniel J Sexton, MD. Septic arthritis in adults. In: UpToDate. Post, TW (Ed), UpToDate, Waltham, MA, 2018. Robert H Shmerling, MD. Evaluation of the adult with polyarticular pain. In: UpToDate. Post, TW (Ed), UpToDate, Waltham, MA, 2018. Connective tissue diseases. In: Pocket Medicine, 6th ed. Sabatine, MS (Ed), Lippincott Williams & Wilkins, Philadelphia, PA, 2016.