Rheumatoid Arthritis & Sjogren's Disease PDF

Rheumatoid Arthritis & Sjogren’s Disease November 2024 Emmanuel Katsaros, DO, FACR  Objectives Identify genetic risk factors that may induce RA. Describe the signs and symptoms of rheumatoid arthritis Describe the unique physical findings of late disea...

Rheumatoid Arthritis & Sjogren’s Disease November 2024 Emmanuel Katsaros, DO, FACR  Objectives Identify genetic risk factors that may induce RA. Describe the signs and symptoms of rheumatoid arthritis Describe the unique physical findings of late disease and organ complications of RA Discuss the pathogenesis of disease, the genetic risk factors, and important cytokines that induce inflammation List the radiographic characteristics of early and late RA List various treatments of RA and their mechanism of action Rheumatoid Arthritis A chronic systemic and destructive inflammatory arthropathy Epidemiology Prevalence: 0.5%-1% of US population Differences exist in the prevalence rates within a country Higher rates in Native Americans such as the Pima tribe Prevalence in Africa and Asia may be 0.2-.4% Females to Males: 2-3:1 Incidence: 40/100,000 per year Peak onset is the 5th and 6th decade of life. Plateaus and then drops after the age of 75. Mortality – Why is RA important to identify and treat early? Prior to aggressive treatment strategies: Mortality rates were comparable to having Stage 4 Hodgkin’s Lymphoma or three vessel cardiovascular disease. Mortality mostly came from cardiovascular disease, infection, and malignancy. Mortality has since improved RA: Signs and Symptoms-– How does a patient with RA usually present? Symptoms Signs DOES NOT get better with rest Restricted movement Pain is all day Swelling with inflammation Significant morning stiffness Synovial fluid: white cell count > 2,000/ μL (>20 min) and after inactivity (gelling) Usually polyarticular (>than 4 Fatigue, Generalized Weakness Joints) A gradual onset is most common Fever & Weight loss can be seen What is the joint pattern of involvement in RA? Usually polyarticular (>than 4 Joints) Involving the wrists, metacarpophalangeal (MCP), and proximal interphalangeal (PIP) joints, metatarsal joints of the feet. Later hips, knees, ankles, elbows, and shoulders are involved. Also involved the upper c-spine, TMJ, SC Joints Comparison of the Hand Involvement RA OA Hand Involvement Swollen MCPs and PIPs Swan neck Boutonniere Ulnar deviation Mutilans Radiographic Characteristics Inflammatory Arthritis Osteoarthritis Non-Articular Symptoms  Inflammation of the uvea, which Uveitis includes the iris, ciliary body and choroid Anterior uveitis aka “iridocyclitis” or “iritis”: affects the iris and the ciliary body. Posterior uveitis aka “chorioretinitis”: affects the retina and choroid.  Ocular -Most common ocular involvement in RA is keratoconjunctivitis sicca (KCS) (10- 35%) -Episcleritis: Appears acutely and causes eye redness and discomfort -Scleritis: less common, but is correlated with vasculitis, long-standing arthritis and active joint inflammation. Usually, painful. Scelromalacia Anterior Uveitis. Painful Episcleral nodulosis  Cardiovascular Myocarditis: Symptoms of chest pain, exercise intolerance, tachycardia and a rise in cardiac biomarkers. Rare Pericarditis: is uncommon and if present is most often seen on echocardiogram. Coronary artery disease. RA is an independent risk factor for CAD. Pt with RA have a higher risk for myocardial infarctions independent of other risk factors that they may have. Heart Failure: 2 X More common in RA patients compared to those without RA. Failure is mostly from preserved ejection fraction (HFpEF) Nodules: Can be present in the pericardium, myocardium, and valvular structures. Symptoms are rare, but heart block and sudden death can occur.  Pulmonary Pleural involvement is found in up 73% of RA patients, but only 23% of patients had pleuritic chest symptoms. 5% were found to have pleural effusion. Pleural effusions: Exudative with a high protein Low WBCs, low glucose and +RF Symptoms are pleuritic chest pain, shortness of breath. Interstitial Lung Disease: Long-standing, nodular, seropositive disease. Often associated with smokers Lung Nodules can occur in the lungs. Caplan syndrome is when there are multiple nodules in patients exposed to dust from coal, asbestos, silica Vasculitis Hematologic Abnormalities Anemia of chronic disease Thrombocytosis Thrombocytopenia is rare in RA, except with drug treatment or Felty's syndrome Eosinophilia Pulmonary complications may be associated with eosinophilia Felty's Syndrome RA in combination with splenomegaly and leukopenia In patients with long-standing, seropositive, nodular, deforming RA Bacterial infections are common in Felty's syndrome Immune complexes coat granulocytes, which results in their sequestration and reduced survival  Osteoporosis Prevalence: Up to 30% of patients Inflammation activates osteoclasts Note: Earlier bone loss is periarticular bone loss due to inflamed joints. Radiology Assistant.com Laboratory Features Sedimentation rate: the distance in millimeters erythrocytes travel from the top of a test tube in one hour. When erythrocytes coated with inflammatory proteins, they cluster and sediment faster. C-Reactive Protein: an acute phase protein that produced by the liver. Less affected by serum components. More stable Increases with in 4-6 hours and normalizes in a week Rheumatoid factor (RF): Autoantibody that binds to FC portions. IgM is the most common. 50% Sensitive and 70% Specific. Laboratory Features Associated with severe RA, including ILD, vasculitis, nodulosis. It is also found in SLE, polymyositis, Sjogren’s, endocarditis, infections (such as HIV, Hepatitis C) hepatic disease , lung disease. Increases with age. Anti-Cyclic Citrullinated Peptide Antibodies (anti-CCP): CCP found in many sites of inflammation, where arginine residues are citrullinated. Found in smokers 67% sensitive and 96% specific 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for RA Genetics and Pathophysiology Etiology – Let’s start with the Instigation of Inflammation There is evidence that an immune reaction occurs early elsewhere in the body, other than the joints, in the setting of some insult to cause systemic inflammation. Mucosal surfaces of the lungs or periodontium are exposed to these insults in the setting of a patient’s “genetic-risk alleles.” “Environmental” insults could be infectious antigens Smoking is also an environmental insult There are likely many unknown antigens that are interacting with certain “at risk genetic-alleles.” Inflammation starts Pathogenesis – An interplay of Genetics and Environment Infection-EBV, oral flora, e-coli, other organisms, Smoking Gender at Birth Genes HLADRB1, PAD14 Inflammation Genetics Concordance rates among identical twins: 12-30% 5%-10% in non-identical twins HLA-DRB1 gene: Found in 70% of the RA pop. 40% of the general population Genetics HLA-DRB1 gene product may be responsible T cell selection and maturation and increased immune response to specific peptides There are certain alleles such as 401 or 404 that are associated with North Europeans 405 and 901 have been found in Japanese, Korean and Chinese populations and are associated with smoking Genetics PAD 14 allele produces peptidyl arginine deiminase type IV which is responsible for citrullination of arginine residues associated with Anti- CCP antibodies, which are highly specific for RA. The Pathogenesis of Synovial Inflammation and Erosions 1. Genetic predisposition, with environmental factors, trigger synovial T cell activation. 2. CD4+ T Cells become activated by antigen- presenting cells (APCs) through the interactions between the T cell receptor and Class II MHC-peptide (signal 1) with co-stimulation through CD28-CD80/86 pathway (signal 2) 3. CD 4+ T-cells differentiate into TH1 and TH 17 cells and produce their own cytokines. 3a. TH1 produces TNFa (also IFN- gamma and lymphotoxin-beta) 3b. TH 17 cells produce IL-17 , TNF-alpha and IL-6 4. T-effector cells stimulate synovial macrophages and synovial fibroblast to secrete proinflammatory mediators, such as Tumor Necrosis Factor- alpha ( TNF-a), which activates osteoclasts to erode bone 5. IL-6 stimulates macrophages to produce TNF- alpha and more IL-6 -IL-6 also stimulates synovial fibroblast proliferation with TGF-beta to produce matrix metalloproteinase (MMP) which cause cartilage damage. All of the cytokines/interleukins play an important role in inflammation 6. CD4 + TH cells activate B Cells, some of which differentiate into autoantibody-producing plasma cells. 7. Immune complexes, perhaps involving RF and anti-CCP Abs, form within the joint and activate complement pathways and thereby increasing inflammation. TNF-alpha then upregulates adhesion molecules in endothelial cells, promoting an influx of leukocytes into the joint. 8. TNF-alpha also upregulates dickkopf- 1(DKK-1), which inhibits pre-osteoblasts (Pre-OB) to form into osteoblasts (OB) 9. Osteoclast (OC) differentiation, responsible for erosions, requires the presence of RANKL, on synovial fibroblast and T-cells, and RANK, found on Pre- osteoclasts(Pre-OC) 10. TNF-alpha also stimulated differentiation of Pre-Osteoclasts and therefore promotes erosions Regulators Two TNF soluble receptors (55kD & 75kD) as a naturally occurring receptor antagonist to down regulate inflammation IL1 Ra - naturally occurring receptor antagonist to IL1 IL-10, IL-4 TGFB (product of Tregs) suppressive cytokine that downregulates inflammation. But it may form more pannus Goal of Therapy: Remission No swollen joints No Tender Joints Not on glucocorticoids Normal ESR Low Global Score Treat To Target Remission or Low Disease Activity Joint Swollen Count Joint Tender Count ESR or CRP Global Score Others Therapies to Treat RA Conventional Disease Modifying Antirheumatic Drugs (cDMARDs) Methotrexate Leflunomide Others: Sulfasalazine, Hydroxychloroquine, Azathioprine Biologics (bDMARDs) Anti-TNF therapies Fully human – Etanercept, Adalimumab Chimeric – Infliximab Other Biologics: Anti-IL-1 agents – Anakinra Anti-IL-6 ra – Tocilizumab, Sarilumab CTLA4-Ig – Abatacept B – Cell Depletion – Rituximab Targeted Synthetic Disease Modifying antirheumatic drugs (tsDMARDS) JanisKinase inhibitors – Tofacitinib, Baricitinib, Musculoskeletal System 2012  Treatment Regimens Monotherapy Tipple Therapy MTX + bDMARD MTX MTX, SSZ, HCQ or tsDMARD Sjogren’s Disease Objective Recognize the clinical features of Sjogren’s Disease Identify the various antibodies that are associated with Sjogren’s Disease List the potential health consequences of Sjogren’s Disease List the differential diagnosis for Sjogren’s Select appropriate treatment management options for a Sjogren’s patient Sjogren’s Disease Chronic inflammatory disorder characterized by lymphocytic infiltrate of the lacrimal (aka keratoconjunctivitis sicca) and salivary glands (aka xerostomia) resulting in dryness of the mouth and eyes. Sjogren’s may be either primary or secondary in association with Rheumatoid Arthritis, Systemic Lupus Erythematosus, or Systemic Sclerosis Demographics –Who gets Sjogren’s Estimated that 1 –2 million people in the US have Sjogren’s Occurrence rate 1/1000 Female: Male ratio 9:1 Age 30-50 Pathogenesis Initial trigger may be a viral infection of the salivary glands, which causes cell death and release of self-antigens. In genetically susceptible people, CD4+ T and B cells specific for these antigens may have escaped tolerance and react against these antigens, resulting in more inflammation and eventual fibrosis of the glands. Initial Signs and Symptoms of Sjogren’s Keratoconjunctivitis 47% Sicca Xerostomia 42% Arthralgia/Arthritis 28% Parotid Enlargement 24% Raynaud’s 21% Fever/fatigue 10% Dyspareunia 5% Oral Manifestations-Why do Sjogren’s patients have poor dentition? Dry mouth, poor dentition Oral candidiasis Burning in the mouth Can’t eat without water Have water present with them all the time Differential Diagnosis Dry Mouth Dry eyes Drugs- Antidepressants, Vitamin A deficiency neuroleptics Age Diabetes Anticholinergic drugs Anxiety AIDS HIV, Hepatitis C Trigeminal Nerve or facial Radiation to the neck paralysis Differential for Bilateral Parotid Enlargement Bilateral Sjogren’s Diabetes Mumps HIV Coxsackie Acromegaly Bulimia Cirrhosis Diagnosis –What are the antibodies associated with Sjogren’s Disease? Rheumatoid Factor + (75%) ANA + (50-80%) Anti-ribonucleoproteins SSA-A (Ro) and SSB (La) in 90 percent of Sjogren’s patients. SS-A and SS-B are sensitive but not specific; they are also seen in SLE. Other Manifestations Involvement of the exocrine glands of the upper respiratory tract leads to dryness of the nasal passages and the bronchi. Higher incidence of pleurisy and desiccation of the tracheobronchial mucus membrane Difficulty swallowing mostly occurs secondary to salivary production Pancreatic insufficiency Other Manifestations -What should be done if an enlarged lymph node is found? Myalgia and arthralgia 40-fold higher risk for lymphoma Lymphomas arise in the salivary glands and the cervical lymph nodes Other Manifestations-What should be done if an enlarged lymph node is found? Biopsy Diagnosis Ocular signs and symptoms and oral symptoms + antibodies Look at the salivary pool Biopsy if there are questions Biopsy of minor salivary should be obtained to confirm the presence of lymphocytic infiltrate Sjogren’s Treatment Dry Eyes: artificial tears, punctal occlusions and pilocarpine or cevimeline Dry Mouth: Pilocarpine and lubricant -Referral to a dentist every 6 months Arthralgia and myalgia: Hydroxychloroquine References 1. Jameson JL et al. Harrison’s Principle of Internal Medicine, 21st ed 2. Hammer GD, McPhee SJ. eds. Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e. McGraw Hill; 2019. Access Medicine (https:// -mhmedical- com.proxy.westernu.edu/content.aspx?bookid=2468&sectionid=19821 9304