Rheumatoid Arthritis PDF

RHUMATOID ARTHRITIS Affects 1% of general population, most common rhumatoid disease. The inflammatory arthropathies are divided into 2 main groups: rhumatoid arthritis and spondyloarthritis. The clinical presentation is inflammatory pain (not mechanical...

RHUMATOID ARTHRITIS Affects 1% of general population, most common rhumatoid disease. The inflammatory arthropathies are divided into 2 main groups: rhumatoid arthritis and spondyloarthritis. The clinical presentation is inflammatory pain (not mechanical pain, due to osteoarthritis). Inflammatory arthropathies: Monoarthritis → 1 joint affected Oligoarthritis → 2-4 Polyarthritis → 5 Arthritis can be proximal or distal. Symmetrical or asymmetrical → main difference between RA (symmetrical) and SA (asymmetrical). Inflammatory pain starts during night (peak of cytokine production in early hours of morning). Rubor, tumor, dolor, calor. Involvement of peri-articular tissues. While mechanical pain (osteoarthritis) starts during the day, aggravated by physical activity. Brief morning stiffness. The joints affected in inflammatory arthropathies are mainly the mobile joints (also called ‘ synovial joint’ or ‘diarthrosis’). These joints have a synovial membrane, composed of an intimal layer and the subintimal layer: Intima: contains 1-2 rows of cells composed mainly of synovial macrophages that are used as APCs, and synovial fibroblasts with synthetic capacity (produce hyaluronic acid, lubricin and other substances of the matrix). RHUMATOID ARTHRITIS 1  Subintimal layer: made of loose connective tissue. The synovial membrane produces synovial fluid, important for nutrition of chondrocytes and protection of the cartilage (flexibility of the joint and non- adherent lubrification). Physiologically, the synovial fluid is found in small amount in a normal joint (5mL in the knee). In an inflamed joint, we can find 60-100mL. Only diarthrosis can be inflamed, because only them have a synovial membrane. Definition Rhumatoid arthritis is a chronic systemic autoimmune inflammatory disease of unknown etiology. Affects diarthrodial joints (movable joints). Can be really severe if not properly treated. Bone damage, erosion, deformities create a disability. Introduce early treatment to prevent deformities. There is an invasion of inflammatory cells into the synovium leading to synovial hyperplasia and edema called ‘pannus’ → the synovial membrane grows and enlarges in cells. The pannus of synovial membrane is responsible for bone erosion. Affects mainly small joints (inter-phalangeal, metacarpo-phalangeal, wrist, ankle) and medium joints. Sometimes, also large joints like the knee. As all inflammatory arthritis, the chronic inflammation favors atherosclerosis. These patients have a high risk of MI and strokes, at a younger age relatively to the general population. Epidemiolgy The prevalence is 0,5-1% in Caucasian, and 5% in native americans. It the most common polyarthritis (>4 joints are involved). Sex: like in every autoimmune disease, higher prevalence in fertile female (so estrogens are involved in autoimmune diseases), 2,5 : 1 ratio. This ratio is even greater in SLE. RHUMATOID ARTHRITIS 2  Age: peak of incidences is found between the 40-60 years-old (midlife). But it can be found in younger or older individuals. If the disease occurs before 16 years-old, it is called idiopathic juvenile arthritis (covered in another lecture). Pathophysiology Main characteristics of RA: Autoantibody production → Rhumatoid Factor + ACPA (anti-citrullinated protein antibody) Pannus (synovial inflammation) Cartilage and bone destruction due to the inflammatory process. If not treated, it can cause permanent damage, deformity and disability. Systemic features: CV, pulmonary, psychiatric problems. RA is a multifactorial disease. It requires a genetic predisposition and several environmental factors can stimulate the development of the disease. These include: Cigarette smoking (fundamental for appearance of disease) Infections, mainly periodontal infections (due to pseudomonas Gingivalis) These factors are probably involved in the breakdown of tolerance to self molecules and the production of autoantibodies → will eventually lead to clinical manifestations. Studies show RF and ACPA autoantibodies can be detected in the serum years (4-5 years) before the clinical manifestation of the disease. Etiology Autoimmune disease means there is a breakdown of immunological tolerance towards self. The trigger initiating this breakdown is unknown. Presence of autoantibodies can be seen years before clinical onset. RHUMATOID ARTHRITIS 3  Genetic predisposition → a lot of gene polymorphisms are identified, most importantly (higher odds ratio) is HLA-B1 (shared epitope). RHUMATOID FACTOR It is an antibody directed against other antibodies. Recognizes the Fc fragment of other antibodies. But it is NOT specific for RA, we can find RF in other autoimmune diseases (Sjogren, SLE) or infectious diseases (HIV, hepatitis) and in normal heahlty people (15%). It is NOT sensitive either, since it can be found in only 70% of patients with RA. ACPA Very specific (close to 100%), they can be found only in patients with RA. But NOT very sensitive, they can be found in only 80% of RA patients. ACPA means Anti-citrullinated protein antibody. Citrullination occurs after translation of proteins due to peptidylarginine deiminase (PAD) enzyme, that converts Arginine into Citrulline. Mostly occurs in dying cells (NETosis, apoptosis, necrosis, autophagy). Environmental factors (smoking, infections) lead to the citrullination of host proteins, cross-reactivity and production of antibodies against the citrullinated residues. ACPA and RF can be present in blood years before clinical onset. Based on the presence of antibodies or not, we divide RA patients into seropositive (those positive for RF, ACPA or both) and seronegative patients that have the clinical characteristics of RA but no auto-antibodies in the serum. About 25% of RA patients are seronegative. Anti-CarP antibodies Anti-carbamylated protein antibody was discovered recently. They are antibodies against carbamylated proteins, a non-enzymatic process that converts lysine to homocitrulline (unlike citrullination which is an enzymatic modification), in the presence of cyanate. RHUMATOID ARTHRITIS 4  Cyanate increases NETosis. Anti-CarP are found in about 45% of the patients with RA and in 30% of the seronegative patients. RA begins outside of joints. Most relevant sites: Lungs Smoking is correlated with risk of RA. The bronchoalveolar fluid in smokers contains a lot of citrullinated proteins. The presence of smoke allows the citrullination of proteins in the alveoli that initiates autoimmunity in genetically predisposed individuals. Smokers who have 2 copies of HLA-DR B1 (shared epitope) have great risk to develop RA. Shared epitope → 5 AA sequence from residue 70 to 74 in the DR-beta chain of HLA, that decides where the peptide binds (HLA presents peptides to cells). This modification in the pocket for binding of peptides determines an increased affinity to bind citrullinated proteins. HLA-DR B1 preferentially binds citrullinated proteins. Citrullinated peptides are bound with higher affinity. Individuals with HLA-DR B1 who smoke are at the highest risk for the development of ACPA antibodies. The association between smoking (for at least 20 years) and ACPA seropositivity is very strong. Risk of RA in smokers is still high 20 years after smoking cessation. Periodontitis Inflammatory disease due to an infectious agents prevalent in general population (10%). It is similar to RA → inflammation of soft tissue (gingival) and bone erosion. Favored by smoking. More prevalent than RA in the general population. The most important infectious agent is Porphyromonas Ginginvalis, is the only bacterium able to citrullinate proteins (possesses the PAD enzyme → peptidyl RHUMATOID ARTHRITIS 5  arginine deaminase). But 60% of RA patients are seronegative (no RF, nor ACPA). RA is a heterogenous syndrome, it can be seronegative (even though it is called autoimmune disease). Pathogenesis As the inflammatory process in the synovial membrane continues, the synovial membrane becomes hyperplastic and hypertrophic (pannus). The intima increases in thickness (up to 4-10 layers of fibroblasts and macrophages, compared to the normal 2 layers). The subintima is infiltrated with many cells of different types, along with neoangiogenesis and increased blood supply. So in RA, the synovial membrane is hyperplastic (sometimes 10 layers) and the sublayers are full of vessels and mononuclear infiltrates. The pannus is invading and destroying the cartilage and eventually the bone, if not treated. Today we have drugs able to stop this process. /!\ Synovial membrane is NOT covering the cartilage. It is at the periphery. In the inflammatory infiltrates, we find plethora of cells → T cells, B cells, macrophages, dendritic cells. T cells can be triggered by APC, and once triggered, they help B cells (who produce antibodies or cytokines). These cells produce a huge number of inflammatory cytokines (especially TNFα, IL-1 and IL-6) and metalloproteinases (ADAMTS) that propagate the inflammation that cannot be counterbalanced by Treg cells. In autoimmune diseases, the Treg (anti-inflammatory T cells, to decrease inflammation) don’t work properly, don’t counterbalance inflammation. The release of metalloproteinases causes the destruction of the hyaline cartilage. RHUMATOID ARTHRITIS 6  Instead, the destruction of the bone occurs mainly due to a particularly strong activation of osteoclasts. Osteoclast activation depends on the binding of RANK ligand to its receptor RANK, (expressed by osteoclasts precursor). RANK-L is produced by many cell types (T cells, macrophages). TNF (important in IBD too) and IL-1 are the most important cytokines in RA. If we add monoclonal antibodies anti-TNF → IL-1 decreases because TNF is the first in the cascade. In the pyramid of inflammatory response, TNF is at the top (over IL-1). Blocking TNF, you can block IL-1. So TNF is more important than IL- 1 in the pathogenesis of RA. TNFα is abundantly produced in the synovial pannus by many cell types (T cells, B cells, NK cells, macrophages…). It amplifies the inflammatory process and additional cytokine production (IL-1, IL-6, GM-CSF), responsible for neoangiogenesis, tissue damage, MHC molecules expression. Patients with RA have an increased presence of TNF in the synovial fluid. IL-6 is responsible for production of acute phase proteins (CRP, fibrinogen, hepcidin). Normal iron. Can have increased ferritin because IL-6 is responsible for increase in hepcidin (storage of ferritin in macrophages). So decrease in availability of iron → decrease of hemoglobin → anemia from chronic disease. NATURAL HISTORY OF RA Genetic predisposition → encounter with an environmental factor → triggering of autoimmunity and presence of antibodies without clinical symptoms → onset of the disease. 1st stage: genetically predisposed, possesses the shared epitope (genetic risk factor). 2nd stage: environmental risk factors. Started smoking, or periodontitis. 3nd stage: breakdown of self tolerance. 4th stage: clinical manifestations. Pain. RHUMATOID ARTHRITIS 7  Clinical features 1. Constitutional symptoms Like other inflammatory arthritis, the initial onset could be accompanied by constitutional symptoms like fatigue, anemia, weight loss. 2. Arthritis RA manifests at first as painful swelling and stiffness of the small joints which are involved in a symmetric manner. Polyarticular → the main joints involved are the proximal interphalangeal joints (PIPs) and the metacarpophalangeal joint (MCP) while the distal joints are spared (unlike the spondyloarthropathies). Additive → with time, more and more joints will be involved. Centripetal → from peripheral joints to axial joints. Only in the elderly there can be a polymyalgia-like manifestation (involvement of shoulders and hips). The only axial joints that could be affected is the atlanto-dental joint (C1-C2), because it is the only joint of the spine with a synovial membrane. Subluxation of the dentum can compress the medulla oblongata due to pannus formation. This is one of the severe complications of RA. So, RA follows a polyarticular symmetrical additive and centripetal trend. Exceptions: Palindromic appearance → for some months, alternance of flare ups and remission. Non persistent. Polymyalgia-like onset → starting from the core instead of the periphery. RHUMATOID ARTHRITIS 8  Not every patient has the same disease. Some have mild/moderate → treat accordingly. 3. Bone erosion The natural history of RA involves erosions of the bone tgat can cause permanent and irreversible deformities and disabilities if no treatment. Bone erosion are the most typical distinctive anatomical lesion of RA. Develops quickly in early stages of RA, and progresses over time. Progressive joint destruction and deformities (triangle feet) means disability in daily activities. To recognize erosion → follow cortical bone on X-ray. Any interruption in cortical bone is erosion. Erosion is due to the pannus. Today it is still not reversible, erosion is forever. Erosion is fast, after 6 month onset of the disease (40% within 6 months, 60% in a year). Preventing erosion means preventing disability. At the beginning, the disability is caused by pain due to inflamed joint (painful so difficult to move). But then it will be due to erosion and become irreversible. Today with the medications (biological drugs) we can prevent the occurrence of bony erosions. In a few extra months the bone damage can increase significantly, so start treatment AS SOON AS POSSIBLE. Examples of deformities In early RA, we have pain, morning stiffness, swollen joints (not damaged yet). The 2nd proximal inter-phalangeal joint is one of the most affected (distal is spared in while it is affected in SA). Volar subluxation (hand deformity) RHUMATOID ARTHRITIS 9  Boutonnière deformity of the finger: flexion of PIP joint and hyperextension of DIP joint. Swan neck deformity: opposite of Boutonnière. Flexion of DIP joint and hyperextension of PIP joint. Triangle feet: plantar subluxation of metatarsal heads Patients start with paracetamol and NSAIDs which can help with the pain but DO NOT prevent damage to the cartilage and bone. 1st treat pain, then treat the disease. RHUMATOID ARTHRITIS 10  4. Extra-articular manifestations (systemic disease) Vasculitis, Amyloidosis, Interstitial lung disease, Serositis, Episcleritis. Rhumatoid nodules: in skin. They appear at bony prominences or juxta- articular. They are the expression of a vasculitis process. Histologically → central fibrinoid necrosis, chronic CT fibrosis. Pulmonary manifestations Interstitial lung disease (lung fibrosis): test at auscultation. Velcro sound means fibrosis. In presence of this sound → require CT scan. Can also request spirometry with VLCO (carbon monoxide examination → normally 80%, decreases in restrictive diseases). Ground glass opacity means inflammation and cellular infiltrate in alveolar spaces, but no damage (could be reversible). Areas of honeycombing → fibrosis (irreversible). Non-specific. We ask for CT because X-ray is not able to discriminate ILD. Rhumatoid lung nodules: patients are frequently smokers, so nodules can also be cancer. Multiple nodules suggest an underlying disease, while a solitary nodule is more suggestive of cancer. Sometimes need biopsy to differentiate. Nodules in RA can present cavitation (predispose to infections → mainly fungal infections, aspergillus). Should rule out lung infections that could cause cavitations → TB, staphylococcus pneumoniae. Cutaneous vasculitis: inflammation of vessel wall. In RA, small vessels are involved → small signs of vasculitis. Eye manifestations: scleritis and episcleritis. Scleritis → most severe, red eye with pain, is an emergency. Interosseous muscle atrophy Renal amyloidosis (secondary amyloidosis) Fetly’s syndrome (rare variant of RA): triad of chronic arthritis, splenomegaly, granulocytopenia (leukopenia → high risk of infections). The risk is linearly activated with disease activity. Paradoxically, the risk of infection decreases when starting immunosuppressants. RHUMATOID ARTHRITIS 11  Heart involvement in RA: accelerated atherosclerosis. Appearing before the general population. Increased risk of MI, stroke, congestive heart failure. To reduce the risk, treat RA. Infections: patients with RA have a higher risk of infections. This occurs due to reduced efficiency of the immune system during generalized inflammation or due to drug-induced immunosuppression. Diagnosis RA score Diagnosis is based on global criteria. RA if this score is >6. Number of joints involved (0-5) → the more joints involved, the higher the probability of having RA. Serology (0-3) → RF and ACPA in the serum Inflammatory markers (0-1) → CRP and ESR Duration of symptoms (0-1) → 6 weeks threshold, since RA is a chronic disease. Lab tests CBC: anemia, leukocytosis, thrombocytosis Inflammatory markers: CRP (>5mg/dL) and ESR (>20 mm/h) Creatinine (kidney test) Transaminases (liver test) Autoantibodies (RF and ACPA) ANA (antinuclear antibodies): differentiation with SLE and Sjogren’s syndrome. Could be positive in 20% of RA patients. If positive, you should RHUMATOID ARTHRITIS 12  test the subtype of ANA. AMA (anti-mitochondrial antibody) Differential diagnosis Psoriatic arthritis Spondyloarthropathies Polymyalgia rheumatica with peripheral arthritis Reactive arthritis Acute sarcoid arthropathy (Lofgren’s syndrome → involvement of ankle) SLE Imaging X-ray At beginning of disease (6 weeks), you ask for X-ray because 40% of patients develop erosion in 6 months → need a baseline X-ray to compare with after. Hands, wrists, foot, additional joints if affected (like knees), bilateral X-ray. There is a narrowing of the joint space (NOT ENLARGED) because inflammation (pannus) is inside the space. At the beginning the damage affects the cartilage (decrease of cartilage → narrowing of the space). After cartilage → bone erosions happen in fingers and wrist. With time → deformities, big erosions. X-ray is 2D, so sometimes it does not show erosion → ask for CT (shows big erosions). CT scan If erosions are not clearly visible with X-ray → ask for CT scan (best modality to study the bones). A small erosion on an X-ray might actually be large erosions that will be apparent only on CT. However, we ask for a CT scan only in a few patients, because the benefits of imaging must be balanced with the risk of radiation exposure. RHUMATOID ARTHRITIS 13  Ultrasound (Power Doppler) To assess the level of inflammation (synovitis) → US (cheaper and more sensitive than MRI) → increase of fluid in the joint. Score → grade 1, 2, 3 if the quantity of fluid is increasing. Synovial proliferation appears in gray. Power Doppler positivity (+) means intense inflammatory activity, it measures hypervascularization and correlates with bone damage. Mainly used for the purpose of follow-up, to see the decrease in the level of inflammation. Indexes of disease activity Some patients have mild, moderate, severe disease. Unfavorable prognostic factors are: High disease activity High CRP and ESR Many joints involved Presence of RF and or ACPA (APCA is a strong predictor for the presence of radiographically apparent bone damage) Pesence of erosions at the 1st X-ray Positive Power Doppler (+) Failure of 2 or more csDMARDs therapies Composite indexes of disease activity: Disease Activity Score (DAS) and DAS28 (28 joints). In clinical practice, we use DAS28. Every time, for every patient examination. The higher the DAS28, the higher the risk of radiological progression. It takes into account: RHUMATOID ARTHRITIS 14  Number of swollen joints (out of 28) Number of tender joints Patient’s global health assessment on a scale of 0-100 describing the disease in the past week Presence of acute phase reactants The score is then calculated, and is used to assess the level of severity of the disease: DAS28 score >5,1 → high activity of the disease DAS28 of 5,1-3,2 → moderate disease activity DAS28 of 3,2-2,6 → low disease activity DAS28