Disease

Clinical Syndrome/ Epidemiology

Antibodies

Laboratory/ Radiology

Genetics

Pathology

Rheumatoid Arthritis

Hypertrophy of synovial lining (pannus),which invades and erodes contigous cartilage and bone. Subintimal area of synovium Northern European : Symmetrical pain and sweling of infiltrated w/ inflammatory HLA DR4 Rheumatoid factor sm joints; progresses to larger cells and angiogenesis Southern European: (IGM against IgG) joints. Morning stiffness; occurs. Proteolytic ESR and C-Reactive HLA DR1 rheumatoid nodules. Weight loss, and anti-CCP. enzymes made by synovial Protein elevated Shared Epitope fever, fatigue. Other organs lining cells, chondrocytes and Other antibodies involved ( scleritis, episcleritis, (QKRAA, etc) maybe a PMS impair integrity of include: anti-collagen (markers of vasculitis, pulmonary nodules,etc, I, anti-aggrecan, anti- inflammation). marker of severity; not cartilage. Bone erosion via pericardial effusions, decreased found w/high cytokines (RANK ligand BiP2, anti-G6P sensory and motor fxns). Occurs prevelance in AA pts w/ interacts w/ RANK receptor isomerase, ANA mostly in women in their 40s-50s. RA. on osteoclasts); proteases from mf and fibroblasts degrade collagen. Synovial fluid w/ PMNs while synovial tissue has lymphocytes and mfs

Gout

Mostly in men Acute onset is painful, w/ redness, warmth, swelling that might be confused w/ cellulitis. First attack usually presents as monoarthritis, usually podagra. Fever and chills may occur. In chronic gout the attacks are more freq and longer. Tophi (collections of UA) in joint and soft tissues around it. GOUT ATTACK INCITED BY: trauma to the joint, sepsis, stress, bedrest, alcohol, dietary indiscretions. GOUT ATTACK STOPPED BY: Inactivation of humural mediators, PMNs (lifetime limited), inhibitors of inflammation, UA crystals solubilized by icreased synovial fluid and heat, or soluble mediators may diffuse away

Hyperuricemia (>7mg/dl) is a risk factor.

X-linked Hypoxanthine guanine phosphoribosyltransfera sedeficiency (HGPRT) (which increases de novo purine biosynthesis) leads to Lesch Nyan Syndrome. These children have mental retardation, spasticity, self mutilationa and hyperuricemia. EVOLUTION: Humans don't have uricase bc of lack of salt in our diet in the past and needed hypertension to be a bipedal mammal.

Synovial fluid w PMNs that have phagocytosed monosodium urease crystals. UA crystals are needle shaped and appear yellow when parallel to axis of polarized light (negavite birerefringent)

Osteoarthritis

Most prevalent form of arthritis in US (Knee is 6% and Hip 3%) and it is the main indication for knee and hip replacement surgery. Use related joint pain; brief, selflimited stiffness; audible grating sounds; reduction in range of motion; minimum swelling and warmth. It is a non-inflammatory arthropathy, instead, it is the end-result of degradative and reparative process in cartilage and bone. Risk factors include age, gender, race, weight, injury, and physical activity (prosective Cohort of Hokins med students demostrated the last 3 factors)

Main radiographic feature: Joint space narrowing and osteophyte (spur).

Focal loss of articular cartilage. There is a hypertrophic reaction in Inherited predisposition. subchondral bone and at the Candidate genes may joint margin. All tissues of the encode cartilage joint are involved. proteins like: COL2A1, Cartilage is made of 70% Type II procollagen water which provides load gene support. Collagens and proteoglycans provide tensile strength.

Enthesopathy: Inflammation at bony insertions of ligaments, tengons and fascia; results in Spondyloarthropathies tendonitis or sausage -like swelling of the digits. These enthesopathies are unique to spondyloarthropaties

HLA-B27 Even though HLA-B27 is found in 8% of caucasians, only 2% of those develope; this haplotype is less common in AA and Antigen derived from bacteria Asians. might be found in affected 63% concordance in joints. monozygotic twins; there are about 30 different subtypes of HLA-B27. B-pocket in HLA-B27; Arginine on position 2 binds to this pocket.

Starts as sacroilitis and progresses up spine. There is osteophyte formation and eventual fusion. There is restricted chest Ankylosing Spondylitis expansion, and shoulders are 'stooped.' There is limited range of motion in neck and breathing is more diaphragmatic. Shober test is positive (can't flex spine well)

X-Ray: Squaring of vertebrae. In advance disease can see bamboo spine and bridging osteophyte. HLA-B27 in 95% In the sacrum there is feather-like calcification at the ligament/tendon insertion

Cartilage is eventually replaced by bone

Reactive Arthritis

Joint inflammation 1-2 wks after infection which involves mucosa. Infectious agents include Chlamidia, Salmonella, Yersinia enterocolitica, Campylobacter, Shigella flexneri. The disease has systemic feaures like: keratoderma blenorrhagica, uveitis and conjunctivitis, lover's hill, cardiatitis (rare). Usually good prognosis, but 30-70% may continue w/ symptoms

HLA-B27 in 50%

Psoriatic Arthritis

10-15% of psoriasis pts (skin before arthritis). There is variable peripheral arthritis; DIP involvement, dactylitis (sausage like) are unique. Nails are also altered (distropic nails and dactylitis); there is back involvement in 40% of pts. Incidence in men and women alike of all ages.

HLA-B27

CD8+ T cells predominate in skin and synovium

Enteropathic Arthritis

Inflammatory arthritis associated w/ inflammatory bowel disease (ulcerative colitis and Chron's), celiac disease, intestinal bypass surg, and infectious enteritis. Monoarthritis is common; arthritis occurs together w bowel symptoms. Can see sacroilitis, spondylitis in a subset.

HLA-B27

SLE

Begins w non-specific sympt of inflammation (fatigue, fever, weight loss, lymphadenopathy) and then gradual onset of specific sympoms. Usually 4 out of 11 specific symptoms to make dx. Specific sympoms include: skin (ptosensitivity, alopecia), nonerosive arthiritis, serositis, hematologic (hemolytic anemia, leokopenia, thrombocytopenia), neuro (seizures, etc). 90% of pts w/SLE are womenchildbearing years.

ANA (staining dilutions of 1:640 are very uncommon in ANA and auto-Ab normal people) replaced LE test. Antibody response is diverse and exhuberant.

Flares usually involve the same sympoms as the intial onset, but get worse.

1st auto-Ab are nonspecific and occur years before onset of symptoms (ANA & antiphospholipid like cardiolipin [FP syphylis serology]) 2nd auto- Ab are specific and occur close to onset of symptoms (Sm, RNP like Ro and La, anti-dsDNA)

Pathologies are diverse and depend on the tissue(s) involved. Mechanisms of tissue damage include Immune complex deposition[activate classical complement pathway], Direct Ab-mediated pathologies[Ab against RBCs cause hemolytic anemias; autodsDNA antibodies can crossreact w/ glutamate receptor and bring CNS symptoms; Ab binding to other cell-surface receptors/ECM antigens can cause damage], Cellular cytotoxicity, Cytokinemediated tissue dysfunction, Vascular injury w/ compromise of blood supply.

Scleroderma

4:1 Women/Men ratio; onset usually around 40 or 50 ys. Can be localized or systemic. If it is systemic it can be limited or diffuse. Can have involvement of skin, Raynaud's, GI, Lung (fibrosis), Heart, Kidney and Musculosk. CREST is limited scleroderma. Early symptoms of scleroderma include fatigue, musculosk discomfort, Raynaud's, Digital ulcers and skin changes. Can see altered naifold capillaries.

In CREST: anticentromere. When heart/kidney are involved: antiMild Anemia. RNA Pol. When Elevated ESR; can diffuse scleroderma+ see ANA. lung fibrosis: antitopo. When muscle is involved: anti-PM-Scl.

High % of pts have family history of autoimmunity. Prevalence in Choctow Native Americans. Concordance in monozygotic twins is 2/40. Likely multiple genes.

Tissue fibrosis and vascular injury. If there is lung involvement, PMNs and eosinophils are present in bronchoalveolar lavage.

Myositis

Inflammation of sk muscle. Include Polymyositis (PM), Dermatomyositis (DM) and Inclusion Body Myositis (amyloidlike inclusion bodies). Myositis presents as subacute muscle weakness; pain isn't common. There are childhood or adult (40-60 ys; mostly women) myositis. Unkown risk factors- viral infections? In DM also see rashes (interface dermatitis), constitutional symptoms and interstitial lung disease; changes in skin and nailfold capillaries.

Auto-Ab in 50% of pts. Anti-Jo1 (targets histidyl tRNA synthetase) in 70% of myositis+interstitial lung disease. Anti-Mi-2 (targets CHD4, a DNA binding protein)

ANA and anticytoplasmic Ab can be seen in dx assays.

Patchy involvement. There is presence of inflammatory cells and there are areas of muscle damage and regeneration. PM: Perimysial inflammation European 8.1 ancestral (around individual ms fibers); haplotype (HLA-A1, B8, more CD8+ and mf C7, DR3; DQ5). predominate too; upregulation Link bw myositis and of MHCI in muscle fibers; infiltrating Tcells degranulate malignancy (sp and release perforing; adenocarcinomas) is restricted repertoire of striking. Incidence of infiltrating and circulating T malignancy usually cells. DM: peaks 1 yr after dx. Perivascular CD4+ infiltrate; perifascicular atrophy (decreased # of capillaries); activation of complement; increased MHCI expression in perifascicular fibers.

Vasculitis

Inflamatory destruction of blood vessels resulting in occlusion/destruction of vessel and ischemia to the tissues that it supplies. Vasculitis is a multisystem disease, w/ subacute onset and prominent inflammation and pain (arthralgia, myalgia and neuralgia) Polyarteritis Nodosum (PAN) may have: mononeuritis multiplex, skin (purpura, ulcers), HTN, renal failure, hematuria or proteinuria, abdominal angina/bleeding, cardiomyopathy, infarction, scleritis, testicular infarction. Wegener's Granulomatosis: Affects sm. blood vessels. Sinus, lung and kidney involvement.

c-ANCA in Wegner's p-ANCA in MPA, Chrug-Strauss and drug-induced vasculitis

Infiltration of vessel wall w inflammatory cells; fibrinoid necrosis of the vessel wall; endothelial proliferation. May result in thrombosis, occlusion, ischemis, aneurysm, rupture or hemorrhage.

Pathogenesis/ Treatment

Viral/Baterial infections may trigger RA (molecular mimicry); no disease-inducing antigen identified yet. CD4+ cells recognize MHCII and secrete IFN-gamma (activate mf). Citrullination of target proteins may increaes their affinity for shared epitopes. Macrophages then secrete IL-1(induces proteases and suppresses synthesis of matrix molecules) and TNF to maintain synovial fibroblast activated. Fibroblast makes IL-6 (induces Bcell maturation), IL-8 (PMNs chemoattractant) and GM-CSF(more mfs). PMNs release Oxygen radicals and depolymerize hyaluronic acid. Kinins case release of prostaglandins; they are algesic agents. C5a is another chemoattractant imp. in pathogenesis of RA. Substance P released by Type C fibers is vasoactive.

TREATMENT: Conventional: Methotrexate, hydroxychloroquine and other cytotoxic agents. Cytokine Inhibitors: 2 anti-TNF monoclonal Ab (Remicade) and one soluble TNF-receptor (Etanercept); IL-1 receptor antagonist. Developing inhibitors of IL-6 and IL-5. Cellular Inhibitors: anti- CTLA-4 Ab (Abatacept) inhibits co-stimulation of Tcells; depletion of CD-20 bearing B-cells by ritixumab.

May be cause by decreased clearance of UA or overproduction. URAT-1 and UAT-1 mediate UA transport in the kidney. Decreased GFR (association b/w gout and hypertension). Diuretics and aspirin increase UA reabsorption. Free UA crystals activate the classical complement pathway attracting PMNs (C5a). UA activates hageman factor -> bradykinin-> increase vascular permeability-> vasodilation -> potentiates prostaglandin release. UA stimulates IL-1, TNF release by mfs, which stimulate production of IL-8 (more PMNs are attracted). UA and mf interaction occurs through Toll-like receptors 2 and 4. UA can stimulate chondrocytes to release NO through TLR-2, which is enhanced by IL-1 and TNF. PMNs exposed to UA release lysosomal enzymes, superoxides and free radicals Leukotriene B4 is another PMN chemoattractant.

TREATMENT Acute: Aspirate joint; NSAIDs, Steroids, avoid high dose colchicine Chronic: Low dose colchicine for prophylaxis, Allopurinol and Probenecid. Future directions: Febuxastat and Uricase (pegylated recombinant porcine uricase)

There is an age related dynamic reaction of joint to insult or injury. The end-product isn't merely a degenerative process, but and attempt at repair. Damage to cartilage is the key in pathogenesis of this disease. Chondrocyte plays a central role, but we don't know what inititiates the process. Cytokines influence chondrocyte activity; metalloproteases mediate tissue degradation by cleaving matrix molecules. TREMTMENT: May need knee or hip replacement.

Applies for all Spondylarthropathies: HLA-B27 + infections are necessary to trigger similar disorders in rats. Simplest Model: Self reactive peptide in HLAB27 mimics a previously encountered bacterial peptide. However, it is hard to find HLA-B27 reactive CD8+ cells in pts; also Tap isn't required, and CD4+ cells are more important in the rat model of the disease. Novel Model: HLA-B27 can misfold and form homodimers that can bind longer peptides and CD4+ and NK cells may recognize them and become self-reactive. TREATMENT: NSAIDs, deoxycycline, sulfasalazine.

TREATMENT: Anti-TNF; efaluzimab(anti-LFA-1; alafacept (soluble LFA-3)

Pathogenesis involves 4 components: 1. Genetic susceptibility 2. Initiating event in which tolerance to apoptotic cells is broken 3. Amplification- the episodic exposure to self-antigen; in the second phase RNAcontaining complexes are targeted. 4. Damage- as a conseq. of chronic immune complex formation and deposition (in skin, joints, kidney and bv) + cellular cytotoxicity. Apoptotic cells are normally inducers of immune tolerance and are normally cleared in an anti-inflammatory manner.

Apoptotic cells may become immunogenic bc of inadequate generation of toleragenic material bc of deficiencies in cell signaling; deficiency in clearance of apoptotic cells (C1q or Mer tyrosine kinase deficiency, defective mfs, type I interferon signaling defective); generation of distinct autoantigens during apoptosis that were not previously tolerized (cryptic antigens). How is tolerance broken in SLE? 1. Revelation of cryptic epitopes 2. Exposure to self antigens that were proviously ignored bc of low levels or bc they were in a privileged environment. 3. Molecular mimicry TREATMENT Inhibition of immune system (steroids). Rituximab (Toll-receptor lugation, anti-B cell therapies). Hydroxychloroquine (antiTLR).Future: Before disease startes provide toleragen by augmenting apoptosis at basal state; after the disease has started, decrease apoptosis by caspase inhibition and increase apoptotic cell clearance.

Edematous phase-> fibrosis-> damage T-cells (Th2) infiltrate skin bfore fibrosis & become activated. Activated mfs make TGF-beta, which plays important roe; promotes scarring, immunosupression, new vessel development and tumor growth. CTL releases granzyme B, which cleaves auto-Ags and causes apoptosis of ECs (vascular damage), cleave soluble factors and matrix derived factors like fibrilling, destabilizing elastin fibers. Other changes in EC fxn include increased vasoconstriction (endothelin), decrease vasodilators (NO), increase platelet aggregation and vasoractivity. Can also see vessel fibrosis.

During inflammation mediated apoptosis (viral infection), granzyme pathway predominates. Granzyme B may clease autoantigens in a novel manner (cryptic peptides). Damaged, regenerating muscle (myoblast) provides the source of antigen in myositis. (Tolerance is usually developed towards dominant and not cryptic epitopes) Increase of myositis-specific antigen expression in a nascent tumor may lead to generation of T and B cells against those antigens, & in many cases to successful tumor immunity. Muscle damage later on may lead to muscle regeneration and suprathreshold levels of MSA in muscle, reactivating immune responses generated in the initial anti-tumor response.

Immune Complex Deposition: Determinants of immune complex pathogenicity include antigen load, antibody response, RES efficacy (complement), vascular factors (pressure, previous damage, branching) and physical properties of the immune complexes like solubility (if have high Ag/Ab ratio is harder to clear). Examples of immune-complex mediated vasculitis include PAN, SLE, Serum sickness. ANCA-associated Model: ANCA ca bind certain enzymes in primary granules of PMNs and mfs. ANCA produces degranulation of PMNs if they are first primed w TNF (which translocate these antigens to the surface). It is thought that during infection, TNF is released and there is translocation of MPO or Pr3 to PMN surface which generates ANCA antibodies. During the next infection ANCA binds to its Ags causing PMN degranulation and EC destruction

TREATMENT Steroids (prednisone) and cyclophosphamide; but they have many side effects. For PAN pts that are infected w Hep B or C do plasmapheresis to remove immune complexes and then one can taper prednisone and give antiviral therapy like lamivudine. For Wegener's one can think of a therapy in which the B-cells are targeted to eliminate ANCA production.