Joint Pain Module: Rheumatoid Arthritis

Definition and EpidemiologyRisk FactorsPathogenesisClinical Symptoms

It is a chronic inflammatory disease of unknown etiology marked by a symmetric, peripheral polyarthritis.

a chronic systemic inflammatory arthritis that may affect many tissues and organs but principally attacks the joints, producing a nonsuppurative proliferative and inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints.Increased incidence among: Females 3-5x > males Common in 40 to 70 years old *NO AGE IS IMMUNE Age of onset usually 30 to 50 years old

Genetic Factors Specific HLA-DRB1 alleles share a common sequence of amino acids in the third hypervariable region of the chain shared epitope located in the antigen-binding cleft of the DR molecule, presumably the specific binding site of the arthritogen(s) that initiates the inflammatory synovitis PTPN22 encodes a protein tyrosine phosphatase, which participates in activation and control of inflammatory cells, including T cells.

Environmental FactorsSmoking - higher citrullination of proteins in bronchoalveolar fluid*citrullinated proteins - enhance the expression of a neoepitope capable of inducing self-reactivityExposure to silicone dust and mineral oilBacterial antigens mycobacteria, Borrelia, Proteus mirabilis, and Mycoplasma Viral antigens Epstein-Barr virus, retroviruses, parvoviruses

The pathogenic mechanisms of synovial inflammation are likely to result from a complex interplay of genetic, environmental, and immunologic factors produces dysregulation of the immune system and a breakdown in self-tolerance.

1. initiation phase - A variety of stimuli may initiate the initial phase of nonspecific inflammation, which may last for a protracted period of time with no or moderate symptoms.2. amplification phase - When activation of memory T cells in response to a variety of peptides presented by antigen-presenting cells occurs in genetically susceptible individuals amplification of inflammation occurs with the promotion of local rheumatoid factor andother autoantibody production and enhanced capacity to mediate tissue damage3. chronic inflammation with tissue injury

Pathology:

Initially the synovium becomes grossly edematous, thickened, and hyperplastic, transforming its smooth contour to one covered by delicate and bulbous fronds.(1) infiltration of synovial stroma by a dense perivascular inflammatory infiltrate composed of lymphoid aggregates (mostly helper T cells), B cells, plasma cells, dendritic cells, and macrophages (2) increased vascularity due to vasodilation and angiogenesis, with superficial hemosiderin deposits(3) aggregation of organizing fibrin covering portions of the synovium and floating in the joint space as rice bodies(4) accumulation of neutrophils in the synovial fluid and along the surface of synovium (5) osteoclastic activity in underlying bone, allowing the synovium to penetrate into the bone and cause juxta-articular erosions, subchondral cysts, and osteoporosis(6) pannus formation fibrous ankylosis bony ankyloses

The pannus is a mass of synovium and synovial stroma consisting of inflammatory cells, granulation tissue, and synovial fibroblasts, which grows over the articular cartilage and causes its erosion.ARTICULAR MANIFESTATIONS:early morning joint stiffness lasting more than 1 hour and easing with physical activity

Common locations: Hands (PIP,MCP),feet (MTP), wrists, knees, elbows, ankles

Pattern of spread: may be monoarticular, oligoarticular (4 joints), or polyarticular (>5 joints); symmetrically additive

Usually insidious onset

Flexor tendon tenosynovitis is a frequent hallmark of RA and leads to decreased range of motion, reduced grip strength, and trigger fingersUlnar deviation- subluxation of the MCP joints, with subluxation of the proximal phalanx to the volar side of the handSwan-neck deformity Hyperextension of the PIP joint with flexion of the DIP jointBouttoniere deformity flexion of the PIP joint with hyperextension of the DIP jointZ-line deformity- subluxation of the first MCP joint with hyperextension of the first interphalangeal (IP) jointflat feet metatarsophalangeal joint (MTP) involvement

Atlantoaxial involvement: cervical spine cervical myelopathy (-) thoracic and lumbar spine affectation

EXTRA-ARTICULAR MANIFESTATIONS: Constitutional - weight loss, fever, fatigue, malaise, depression, and in the most severe cases, cachexia Subcutaneous nodules most common cutaneous lesion; firm, non-tender, and round to oval, and in the skin arise in the subcutaneous tissue including the ulnar aspect of the forearm, elbows, occiput, and lumbosacral area. Less commonly they form in the lungs, spleen, pericardium, myocardium, heart valves, aorta, and other viscera. Secondary Sjgren's syndrome Pleural disease, the most common pulmonary manifestation of RA Pericarditis (most common), cardiomyopathy Rheumatoid vasculitis normochromic, normocytic anemia Feltys syndrome - clinical triad of neutropenia, splenomegaly, and nodular RA Hypoandrogenism Osteoporosis

Diagnosis Treatment

Rheumatoid arthritis is diagnosed if 4 or more of these 7 factors are present.1) Morning stiffness: Morning stiffness in and around the joints for at least one hour.2) Arthritis of 3 or more joint areas: Swelling or fluid around three or more joints simultaneously. The 14 possible areas are right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints 3) Arthritis of hand joints: At least one swollen area in the wrist, hand, or finger joints.4) Symmetric arthritis: Arthritis involving the same joint on both sides of the body.5) Rheumatoid nodules: Are firm lumps in the skin of people with rheumatoid arthritis. These nodules are usually in pressure points of the body, most commonly the elbows.6) Serum rheumatoid factor: Abnormal amounts of rheumatoid factor in the blood.7) Radiographic changes: X-ray changes in the hands and wrists typical of rheumatoid arthritis, with destruction of bone around the involved joints. However, these changes are typical of later-stage disease.* Criteria 1 through 4 must have been present for at least 6 weeks. Patients with 2 clinical diagnoses are not excluded.

The clinical diagnosis of RA is largely based on signs and symptoms of a chronic inflammatory arthritis, with laboratory and radiographic results providing important supplemental information.

2010 ACR-EULAR criteria yields a score of 010, with a score of 6 fulfilling the requirements for definite RA

LABORATORY FEATURES:-Serum RF: IgM, IgG, and IgA isotypes of RF occur in sera from patients with RA, although the IgM isotype is the one most frequently measured-Serum anti-cyclic citrullinated peptide antibodies: diagnostic specificity approaches 95%

Synovial fluid analysis: Most useful for confirming an inflammatory arthritis, while at the same time excluding infection or a crystal-induced arthritis such as gout or pseudogout Reflects an inflammatory state.Synovial fluid white blood cell (WBC) counts can range between 5000 and 50,000 WBC/L3 ; neutrophil predominance

Joint imaging: plain Xray- juxtaarticular osteopenia, soft tissue swelling, symmetric joint space loss, and subchondral erosions, most frequently in the wrists and hands (MCPs and PIPs) and the feet (MTPs)

MRI- greatest sensitivity for detecting synovitis and joint effusions Ultrasound- ability to detect more erosions than plain radiography, especially in easily accessible joints

NSAIDS - both analgesic and anti-inflammatory adjunctive therapy for management of symptoms; minimize side effects of gastritis and peptic ulcer disease with the use of selective COX-2 inhibitors

Glucocorticoids: Rapid disease control: low-to-moderate doses before onset of fully effective DMARDS therapy Acute disease flares: 12 week burst of glucocorticoids may be prescribed dose and duration guided by the severity of the exacerbation patients with an inadequate response to DMARD therapy: Chronic administration of low doses (510 mg/d) of prednisone (or its equivalent) minimize chronic use of low-dose prednisone therapy owing to the risk of osteoporosis and other long-term complications ACR recommends primary prevention of glucocorticoid-induced osteoporosis with a bisphosphonate in any patient receiving 5 mg/d or more of prednisone for greater than 3 months

DMARDS RA progressionconventional DMARDs: hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide; delayed onset of action of approximately 612 weeksMethotrexate is the DMARD of choice for the treatment of RA and is the anchor drug for most combination therapiesleflunomide - inhibitor of pyrimidine synthesis, appears similar to that of methotrexateHydroxychloroquine has not been shown to delay radiographic progression of disease and thus is not considered to be a true DMARD

RemissionAt any time point, patient must satisfy all of the following: Tender joint count 1 Swollen joint count 1 C-reactive protein 1 mg/dL Patient global assessment 1 (on a 010 scale)ORAt any time point, patient must have a Simplified Disease Activity Index score of 3.3

References: Harrisons Principles of Internal Medicine , 16th and 18th ed Cecil Medicine, 23rd EdRobbins and Cotran Pathologic Basis of Diseases 8th edBates Guide to Physical Examination and History Taking 11th ed