Rheumatoid arthritis

Rheumatoid arthritis

1. RHEUMATOID ARTHRITIS DR ANEES KURIKKAL MD Internal medicine resident 2020/9/23

2. INTRODUCTION Rheumatoid arthritis (RA) : the most common inflammatory arthritis, affecting from 0.5% to 1% of the general population worldwide. RA, a systemic disease, may also lead to a variety of extraarticular manifestations, including fatigue,subcutaneous nodules, lung involvement, pericarditis, peripheral neuropathy, vasculitis, and hematologic abnormalities Early diagnosis of RA is pivotal to prevent damage and complications

3. CLINICAL FEATURES The incidence of RA increases between 25 and 55 years of age, after which it plateaus until the age of 75 and then decreases C/O early morning joint stiffness lasting more than 1 h that eases with physical activity. Small joints of hand and feet are the earliest involved joints The initial pattern of joint involvement may be monoarticular , oligoarticular (≤4 joints) , or polyarticular (>5 joints) , usually in a symmetric distribution. the wrists, metacarpophalangeal (MCP), and proximal interphalangeal (PIP) joints are the most frequently involved joints DIP also can be involved , but is usually a manifestation of coexistant osteoarthritis Flexor tendon tenosynovitis is a frequent hallmark of RA and leads to decreased range of motion, reduced grip strength, and “ trigger” fingers .

4. Ulnar deviation results from subluxation of the MCP joints, Hyperextension of the PIP joint with flexion of the DIP joint (“ swan-neck deformity ”) flexion of the PIP joint with hyperextension of the DIP joint (“ boutonnière deformity ”) Subluxation of the first MCP joint with hyperextension of the first interphalangeal (IP) joint (“ Z-line deformity ”)

5. Inflammation about the ulnar styloid and tenosynovitis of the extensor carpi ulnaris may cause subluxation of the distal ulna, resulting in a “ piano-key movement ” of the ulnar styloid.

6. MTP joint involt is an early feature of RA , but chronic inflammation of ankle and midtarsal areas come later and may lead to pes planovalgus (flat feet ) Atlantoaxial involvement of the cervical spine may cause compressive myelopathy and neurologic dysfunction . RA rarely affects the thoracic and lumbar spine. Extraarticular manifestations may develop during the clinical course of RA in up to 40% of patients, even prior to the onset of arthritis Subcutaneous nodules, secondary Sjögren’s syndrome, interstitial lung disease (ILD), pulmonary nodules, and anemia are among the most frequently observed extraarticular manifestations.

7. CONSTITUTIONAL SIGNS AND SYMPTOMS include weight loss, fever, fatigue, malaise, depression, and in the most severe cases, cachexia the presence of a fever of >38.3°C (101°F) at any time during the clinical course should raise suspicion of systemic vasculitis or infection .

8. NODULES Subcutaneous nodules have been reported to occur in 30–40% of patients and more commonly in those with the highest levels of disease activity When palpated, the nodules are generally firm; nontender ; and adherent to periosteum, tendons, or bursae; developing in areas of the skeleton subject to repeated trauma or irritation such as the forearm, sacral prominences, and Achilles tendon may also occur in the lungs, pleura, pericardium, and peritoneum Are usually benign

9. PULMONARY INVOLVEMENT Pleuritis, the most common pulmonary manifestation of RA, may produce pleuritic chest pain and dyspnea , as well as a pleural friction rub and effusion Pleural effusions : exudative with increased numbers of monocytes and neutrophils ILD may also occur and can be a/w cigarette smoking Recent studies have shown the overall prevalence of ILD in RA to be as high as 12% Usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP) are the main histological and radiologic patterns of ILD PFT : restrictive pattern with reduced DLCO Caplan’s syndrome is a rare subset of pulmonary nodulosis characterized by the development of nodules and pneumoconiosis following silica exposure

10. CARDIAC INVOLVEMENT The most frequent site of cardiac involvement in RA is the pericardium But clinical manifestations of pericarditis occur in <10% of patients with RA Cardiomyopathy, may result from necrotizing or granulomatous myocarditis, coronary artery disease, or diastolic dysfunction. This also may be subclinical and only identified by echo or cardiac MRI Rarely, the heart muscle may contain rheumatoid nodules or be infiltrated with amyloid . Mitral regurgitation is the most common valvular abnormality in RA

11. HAEMATOLOGIC A normochromic, normocytic anemia often develops in patients with RA and is the most common hematologic abnormality ESR, CRP and platelet levels may be elevated Felty’s syndrome is defined by the clinical triad of neutropenia, splenomegaly, and nodular RA and is seen in <1% of patients Occurs in late stages of RA T cell large granular lymphocyte leukemia (T-LGL) may have a similar clinical presentation and often occurs in association with RA., but it presents early The most common histopathologic type of lymphoma is a diffuse large B cell lymphoma (DLBCL) The risk of developing lymphoma increases if the patient has high levels of disease activity or Felty’s syndrome.

12. SECONDARY SJÖGREN’S SYNDROME is defined by the presence of either keratoconjunctivitis sicca (dry eyes) or xerostomia (dry mouth) in association with another connective tissue disease, such as RA. Approximately 10% of patients with RA have secondary Sjögren’s syndrome. RHEUMATOID VASCULITIS typically occurs in patients with long-standing disease , a positive test for serum RF or anti-CCP antibodies, and hypocomplementemia The cutaneous signs vary and include petechiae, purpura, digital infarcts, gangrene, livedo reticularis, and in severe cases large, painful lower extremity ulcerations. Vasculitic ulcers may be treated successfully with immunosuppressive agents Sensorimotor polyneuropathies, such as mononeuritis multiplex , may occur in association with systemic rheumatoid vasculitis.

13. ASSOCIATED CONDITIONS CARDIOVASCULAR DISEASE The most common cause of death in patients with RA is cardiovascular disease. Incidence of CAD and carotid atherosclerosis is higher in RA pts CCF occurs at 2 fold higher rate than in general population OSTEOPOROSIS Osteoporosis is more common in patients with RA than an age- and sex-matched population, with prevalence rates of 20–30%. Inflammation spill over to bone osteoclast activation  generalized bone loss Hip fractures are more likely to occur in patients with RA

14. HYPOANDROGENISM Men and postmenopausal women with RA have lower mean serum testosterone, luteinizing hormone (LH), and dehydroepiandrosterone (DHEA) levels than control populations. Patients receiving chronic glucocorticoid therapy may develop hypoandrogenism owing to inhibition of LH and follicle-stimulating hormone (FSH) secretion from the pituitary gland. Men with hypoandrogenism should be considered for androgen replacement therapy , since they are prone to osteoporosis

15. EPIDEMIOLOGY RA affects ~ 0.5–1% of the adult population worldwide. Incidence has decreased due to proper treatment , but prevalence remains the same RA occurs more commonly in females than in males, with a 2–3:1 ratio Studies hypothesize that estrogen can stimulate production of tumor necrosis factor α (TNF-α), a major cytokine in the pathogenesis of RA.

16. GENETIC CONSIDERATIONS first-degree relative of a patient : risk of RA is 2–10 times greater than in the general population Risk is a/w allelic variation in the HLA-DRB1 gene, which encodes the MHC II β-chain molecule Carriership of the SE alleles ( shared epitope) is associated with production of anti-CCP antibodies and worse disease outcomes. non-MHC genes contributing to the risk of RA  gene encoding protein tyrosine phosphatase non-receptor 22 (PTPN22) Others PAD14, APOM

17. ENVIRONMENTAL FACTORS Most important : cigarette smoking ( relative risk of getting RA 1.5-3.5) Women who smoke (2.5) Risk from smoking related to RF and antiCCP antibody positive disease Periodontitis due to Porphyromonas gingivalis may predispose to RA (citrullination of arginine by peptidyl arginine deiminase (PAD) leads to anti CCP antibody production

18. PATHOPHYSIOLOGY RA is characterised by infiltration of the synovial membrane with lymphocytes, plasma cells, dendritic cells and macrophages. In Lymphoid follicles in synovial membrane , T- and B-cell interactions occur  cytokine release  activate B cells to produce autoantibodies (RF and ACPA) Synovial macrophages : activated by TNF and interferon gamma (IFN-γ) Macrophages  pro-inflammatory cytokines, including TNF, IL-1 and IL-6 Synovial fibroblasts proliferate, causing synovial hypertrophy and producing matrix metalloproteinases and the proteinase ADAMTS-5, which degrade soft tissues and cartilage Prostaglandins and Nitric Oxide in inflamed synovium  vasodilatation  pain and swelling Systemic release of IL-6 triggers production of acute phase proteins by the liver.

19. At the joint margin, the inflamed synovium (pannus) directly invades bone and cartilage to cause joint erosions. Bone erosion is due to osteoclast activation by RANKL Angiogenesis  highly vascular synovium  proinflammatory cytokines  recruit more leukocytes  more inflammation Later, fibrous or bony ankylosis may occur Muscles adjacent to inflamed joints atrophy and may be infiltrated with lymphocytes  progressive biomechanical dysfunction and may further amplify destruction

20. DIAGNOSIS Based on signs, symptoms of chronic arthritis + lab and radiographic evidence ACR- EULAR score >= 6 : definite RA

21. LAB FEATURES Raised ESR,CRP Serum IgM RF : 75–80% of patients with RA; Anti CCP antibody : diagnostic specificity 95%, has significance for worse prognosis SYNOVIAL FLUID ANALYSIS WBC: 5000 and 50,000 / μL (<2000 WBC/ μL in osteoarthritis) Predominant cell : Neutrophil Can confirm inflammation and exclude infection, crystal induced arthritis

22. JOINT IMAGING Useful for diagnosis and for tracking progression of joint damage Plain X Ray : most widely used – shows joint space narrowing “ Periarticular osteopenia” other findings on X ray : 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 and USG can detect synovitis, tenosynovitis, and effusions and has greater sensitivity for identifying bony abnormalities. Power color doppler is an USG based investigation which ca detect erosions

23. CLINICAL COURSE The natural history of RA is complex and affected by a number of factors including age of onset, gender, genotype and comorbid conditions 10% of patients with inflammatory arthritis fulfilling ACR classification criteria for RA will undergo a spontaneous remission within 6 months But majority show a pattern of persistent and progressive disease activity that waxes and wanes in intensity over time More than one-half of patients with RA are unable to work 10 years after the onset of their disease The overall mortality rate in RA is two times greater than the general population, with ischemic heart disease being the most common cause of death followed by infection Median life expectancy is shortened by an average of 7 years for men and 3 years for women compared to control populations

24. TREATMENT The treatment goal is to suppress inflammation, control symptoms and prevent joint damage. This involves a combination of pharmacological and non-pharmacological therapies Various disease activity scores are employed : Disease Activity Score (DAS), Simplified Disease Activity Index (SDAI), the Clinical Disease Activity Index (CDAI), and the Routine Assessment of Patient Index Data 3 (RAPID3) The medications used for the treatment of RA may be divided into broad categories Nonsteroidal anti-inflammatory drugs (NSAIDs) Glucocorticoids (prednisone and methylprednisolone) Conventional DMARDs Biologic DMARDs

25. GLUCOCORTICOIDS They may be administered in low to moderate doses to achieve rapid disease control before the onset of fully effective DMARD therapy, which often takes several weeks or even months. 1- to 2-week burst of glucocorticoids may be prescribed for the management of acute disease flares Chronic administration of low doses (5–10 mg/d) of prednisone  control disease activity in patients with an inadequate response to DMARD therapy. High-dose : for severe extraarticular manifestations of RA, such as ILD intraarticular injection of triamcinolone acetonide : limited no of affected joints Bisphosphonates to prevent osteoporosis

26. CONVENTIONAL DMARDS DMARDs are so named because of their ability to slow or prevent structural progression of RA. Include : hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide Has delayed onset of action of ~6–12 weeks Methotrexate is the pioneer and can stimulate adenosine release from cells, producing an anti-inflammatory effect Leflunomide, an inhibitor of pyrimidine synthesis : efficacy similar to methotrexate Hydroxychloroquine has not been shown to delay radiographic progression of disease and thus is not considered to be a true DMARD Sulfasalazine can reduce radiographic progression of disease

27. BIOLOGIC DMARDS They are protein therapeutics which target cytokines and cell-surface molecules. TNF inhibitors : first approved biologicals include Infliximab ,Adalimumab ,Golimumab , Certolizumab and Etanercept Anti-TNF agents avoid in active infection or a history of hypersensitivity contraindicated in patients with chronic hepatitis B infection or class III/IV congestive heart failure Screen for TB before starting the drug Never combine with anakinra  severe infections Anakinra, an IL-1 receptor antagonist: came later , rarely used now Abatacept, rituximab, and tocilizumab are the newest members of this class

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