Rheumatologic Disease – Class 2 PDF

Rheumatologic Disease – Class 2 Seronegative Spondyloarthropathies Systemic Lupus Erythematosus BMS 150 Week 5 Video Links Video 1 Video 2 Systemic Lupus Erythematosus “The disease of 1000 faces” ▪ Vast array of presentations and...

Rheumatologic Disease – Class 2 Seronegative Spondyloarthropathies Systemic Lupus Erythematosus BMS 150 Week 5 Video Links Video 1 Video 2 Systemic Lupus Erythematosus “The disease of 1000 faces” ▪ Vast array of presentations and affected organs ▪ Can be acute or present slowly over time ▪ Main organs affected: skin, joints, kidney, and serosal membranes However, almost any tissue can be affected Epidemiology: ▪ Prevalence of ~ 1/2500, onset typically in 20’s and 30’s ▪ Women:men is about 9:1 In the extremes of age (very young, very old) ratio of women to men is approximately 2:1 More common in Hispanic, African heritage SLE – General Pathogenesis Systemic autoimmune disorder characterized by a number of auto-antibodies – specifically antibodies against nuclear components (ANA) ▪ ANAs specific to SLE: Anti-ds DNA Anti-Smith antigen antibodies (antibodies against small ribonuclear particles) Many patients also have other autoantibodies against blood elements ▪ RBCs, platelets, WBCs Around 40-50% of patients also have antibodies to phospholipid-associated proteins SLE - Etiology Genetic predisposition ▪ Monozygotic twin concordance (24%) ▪ Familial and HLA (on chromosome 6) clustering HLA DR3, HLA A1, HLA B8 Exogenous factors ▪ Drug exposure FYI: 400 medications that can cause this condition – most common are procainamide, hydralazine, quinidine, and phenytoin ▪ UV and irradiation ▪ Estrogens – much more common in women mechanism is not known SLE - Pathogenesis Pathophysiology ▪ Failure of self-tolerance (mechanism is not well- elucidated) CD4+ cells that recognize nucleosomal components, self-reactive B-cells are found in animal models and human patients Lots of type I interferons present – possible that own DNA reacts with TLRs (on dendritic cells and antibodies) leading to a Th-1 response against own tissues ▪ Inadequate clearance of self antigens may play an important role Deficient C1q may impair the ability of macrophages to clear apoptotic bodies → prolonged presence of nuclear material in the extracellular space SLE model Pathophysiology Environment: UV light worsens many dermatologic symptoms (altered DNA, enhanced IL-1 production by keratinocytes) Overall view: inadequate clearance of apoptotic cells combined with presence of autoreactive T-cells and B-cells that recognize these cellular components TLRs seem to recognize nuclear components, leading to continual activation of APCs and inflammation SLE So what damages tissues? ▪ Autoantibodies likely play a central role Immune complex damage in the glomerulus and in many other small blood vessels throughout the viscera ▪ What type of hypersensitivity is this? Autoantibodies can also opsonize and destroy RBCs, platelets, and leukocytes ▪ What type of hypersensitivity is this? Acute necrotizing vasculitis involving capillaries, small arteries and arterioles may be present in any tissue ▪ Arteritis is characterized by fibrinoid deposits in the vessel walls, thickening and luminal narrowing - lead to ischemia  SLE: Clinical features Hematologic: Anemia and thrombocytopenia are the most common problems Lymphopenia – immunosuppression is rare, though  SLE – Clinical features Arthritis: inflammation of synovium that does not tend to erode the cartilage of the joint or cause ankylosis Skin: sunlight worsens the rash – Malar rash in 50% of patients – Urticaria, bullae, maculopapular lesions, and ulcerations can also occur – Edema, degeneration of the epidermis, and vasculitis can be present Pericarditis and pleuritis (serositis): – mesothelial surfaces can be covered with fibrinous exudate – Later they become thickened and coated with fibrous tissue that can obliterate the serosal cavity https://en.wikipedia.org/wiki/Malar_rash#/media/File:Lupusfoto.jpg SLE – Clinical Features Cardiovascular: ▪ Myocarditis (mononuclear cell infiltrate) and valvular damage (valve leaflets thicken and can shorten) ▪ Worsened atherosclerosis ▪ Warty vegetations occur on the inflow or outflow surfaces of the mitral and tricuspid valves → stenosis & regurgitation Valvular abnormalities are common – they can be subtle or quite significant SLE - Clinical Manifestations Nervous system: ▪ Difficulties in memory and reasoning, mood disorders, headaches ▪ Seizures and psychosis can be present during flares Spleen ▪ Moderate splenomegaly ▪ Perivascular fibrosis around arteries → onion-skin appearance Pleuritis ▪ Pleural effusions ▪ Interstitial pneumonitis ▪ Diffuse fibrosing alveolitis SLE – Clinical Features Renal ▪ A range of complicated renal pathologies can be present in lupus – which we’ll discuss in renal pathology Immune complexes can be deposited in the glomeruli, tubules, around peritubular or glomerular capillaries, or even around smaller vessels Not uncommon for the renal complications to result in kidney failure – major cause of morbidity in this disorder  Discoid lupus Skin manifestations of lupus with few to no systemic symptoms – Discoid lesion: skin plaques showing varying degrees of edema, erythema, scaliness, follicular plugging, and skin atrophy surrounded by an elevated erythematous border SLE – clinical course Extremely variable – hard to know which complications are going to arise ▪ Skin complications and hematologic abnormalities are most common ▪ Other complications – renal and cardiac disease, neurological abnormalities – are less common but have serious morbidity ▪ Infections are common – likely due to immunosuppressive medications as well as impaired immune function Time course: ▪ Rarely acute and fulminant, with death in months – weeks ▪ Usually a progression of remissions and flares spanning years – decades Survival at 10 years is about 80% Most common causes of death are renal failure, infection, and coronary artery disease Seronegative Spondyloarthropathies Group of disorders characterized by: ▪ Lack of serum markers (i.e. Rheumatoid Factor, ANA, dsDNA) ▪ Association with HLA-B27 (most of the diseases in this category) ▪ Inflammation of synovial joints Usually involves inflammatory back pain – arthritis of the sacroiliac joints and the inter-vertebral joints are common Seronegative Spondyloarthropathies Overview: Ankylosing spondylitis ▪ Most common, causes ankylosis of sacroiliac and intervertebral joints Reactive arthritis ▪ Follows urethritis or gastroenteritis, involves arthritis and uveitis Psoriatic arthritis ▪ Associated with psoriasis, often involves interphalangeal joint arthritis Arthritis associated with IBD ▪ Extra-intestinal manifestation of Crohn’s disease or ulcerative colitis HLA B27 and spondyloarthropathies Population or Disease Entity HLA-B27 –Positive Healthy whites 8% Healthy African Americans 4% Ankylosing spondylitis (whites) 92% Ankylosing spondylitis (African 50% Americans) Reactive arthritis 60-80% Psoriasis associated with spondylitis 60% IBD associated with spondylitis 60% Isolated acute anterior uveitis 50% Undifferentiated spondyloarthropathy 20-25% Ankylosing spondylitis Ankylosing = fusion of a joint – usually through osteophyte formation and calcification of an inflamed synovial joint Spondylitis = inflammation of the intervertebral joints Epidemiology: ▪ Most common of the spondyloarthropathies ▪ Prevalence of 0.1 – 1% of population (much more common in Caucasians) ▪ 2-3 times more common in men Ankylosing spondylitis Pathogenesis Etiology: HLA-B27 thought to be a major risk factor, or genes located around that locus – 90% or higher of those with the disease have this HLA haplotype ▪ Antigen-binding subtypes of HLA-B27 resemble certain molecules of Klebsiella pneumonia – molecular mimicry as a cause? Pathological findings: chronic inflammation at sites of tendinous or ligamentous insertion sites results in: ▪ Joint erosion ▪ Fibrosis of the joint capsule ▪ Ossification of the the capsule, “linking” the bones on either side of the joint Ankylosing spondylitis Clinical findings: Insidious onset of low back pain Onset of symptoms in those younger than 40 years Presence of symptoms for more than 3 months Symptoms worse in the morning or with inactivity (gelling) Improvement of symptoms with exercise Pain is typically poorly localized to the lower back and gluteal region – inflammation of the sacroiliac joint is the major pathological finding ▪ As the name suggests, bony ankylosis of the intervertebral joints is quite common (bamboo spine)  Ankylosing spondylitis Clinical findings: Enthesitis – commonly at site of Achilles tendon insertion, inflammatory joint pain that is typically moderate – severe Other joints involved are proximal, and include: ▪ Hips, shoulders, joints of the chest wall ▪ Involvement of costovertebral joints can result in dyspnea Extra-articular findings: acute uveitis (25 – 30%), aortitis (rare), poor inflation of lungs due to decreased chest wall mobility, spinal fractures  Ankylosing spondylitis Diagnosis: Radiography, history, and PE sufficient to make the diagnosis in most cases Treatment: symptomatic anti- inflammatories ▪ Anti-TNF drugs may slow joint destruction and progression of disease ▪ Surgery to stabilize fractures, physical therapy to aid respiratory function Prognosis: better than RA – most patients can continue to work with the disease ▪ Worse with earlier onset ▪ Impairment of mobility is the main factor that impacts quality of life Reactive arthritis Two types – post-urethritis and enteritis-associated arthritis ▪ Post-urethritis joint inflammation and conjunctivitis Used to be known as Reiter syndrome ▪ Enteritis–associated arthritis: arthritis that occurs after a gastrointestinal infection ▪ Both are strongly associated with HLA B27, both are more common in men Pathological findings: ▪ Synovitis, which can result in severe destruction of the joint surface and underlying bone ▪ Ossification of tendino-ligamentous insertion points Epidemiology ▪ Could be as high as 1% of chlamydial urethritis or bacterial gastroenteritis (especially Campylobacter and Shigella infections) Reactive arthritis Clinical Features: 2-6 weeks after a chlamydial urethritis ▪ Or 2-6 weeks post shigella, salmonella, yersinia, or campylobacter GI infection Joint stiffness and pain are the typical presenting symptoms ▪ Lower back ▪ Ankles, knees, feet ▪ Synovitis of one or a few interphalangeal joints ▪ Some people are unfortunate enough to experience chronic disease – can be as severe and chronic as ankylosing spondylitis ▪ Enthesitis is common  Dactylitis Can result in significant destruction and deformity of a digit Typical of psoriatic arthritis and reactive arthritis ▪ Results in loss of mobility of inter-phalangeal joints - inflammation that is typically asymmetrical ▪ Destruction of joint and bones of the digit occurs in many Psoriatic arthritis – the basics Found in 5 – 30% of those with psoriasis ▪ Prevalence of psoriasis is ~ 1% ▪ Affects both peripheral and axial joints – and as with all spondyloarthropathies, enthesitis is common Dactylitis (sausage finger) present in 20 – 30% Asymmetric, usually first symptoms appear in the fingers and toes ▪ Extra-articular manifestations are not common – main ones are conjunctivitis and iritis ▪ Chronic, flaring disease that often causes significant damage to the digits of the hands