Autoimmune Disorders - RA, Lupus, Scl, SS, Spondylo, etc. Flashcards
If a pt is experiencing back pain related to RA, it is most likely to be isolated to which vertebrae?
C1, C2, C3
*in OA, the spine is much more heavily involved than in RA; and damage to the cervical spine usually occurs after several years of disease
What is rheumatoid arthritis?
A chronic multi-system disease mediated by auto-immune mechanisms. Characterized by persistent inflammatory synovitis (peripheral joints, symmetric distribution) which erodes cartilage and bone.
The disease has a variable course.
What constitutes the diagnosis of rheumatoid arthritis?
> =6 points on the classification scale, which includes points for the following categories:
- Joint distribution (how many large and how many small joints involved)
- serology (negative/low positive/high positive of RF and ACPA)
- symptom duration (>6wks)
- acute phase reactants (abnormal CRP and/or ESR)
Describe the characteristic laboratory features of rheumatoid arthritis.
- Rheumatoid Factor (RF): usually IgM type Ab directed against the Fc portion of IgG; not specific for RA
- Anti-CCP Ab: anti-cyclic-citrullinated peptide antibody produced by synovial B cells; more specific for RA
- ANA: seen in 20% of RA pts
- Abnormal CRP and/or ESR
Describe the characteristic systemic clinical features of rheumatoid arthritis.
fatigue, anorexia, weight loss, weakness, generalized aching and stiffness, low-grade fever
Describe the characteristic articular (local) clinical features of rheumatoid arthritis.
- swelling, warmth, erythema, and pain in the affected joints
- stiffest for at least 30min in the morning
- insidious onset, can begin as intermittent
- not usually migratory but appears in one joint (typically large peripheral joints like the knee), persists, and develops into persistent polyarthritis (characteristically involving wrist and proximal hand)
- synovial fluid analysis reveals exudative yellow fluid, elevated WBCs/neutrophils, and reduced viscosity
- weakened tissues and supporting structures such as ligaments, joint capsules
- may lead to fibrosis of tissues including muscles
- muscle atrophy from inflammation and disuse
- joint deformities under normal forces of muscular traction
Describe the characteristic extra-articular clinical features of rheumatoid arthritis.
skin - rheumatoid nodules, vasculitis
ocular - keratoconjunctivitis sicca (dry eyes), xerostomia (dry mouth), episcleritis and scleritis (like skin nodules but on sclera) (due to lymphocytic infiltration of glands)
Cardiorespiratory - fibrosis, pulm nodules, pleuritis with pleural effusion (common), pericarditis, valve nodules
Neurologic - cervical myelopathy, carpal tunnel syndrome, ulnar tunnel syndrome (Guyon’s canal)
Summarize current thoughts on what factors contribute to development of rheumatoid arthritis.
Genetics (60%) and Environmental (rest). Gene-environment interactions may be multiplicative or additive in RA risk.
Genetics: there are >35 risk loci, with HLA-DRB1 (DR4) contributing ~30% genetic risk, other inflammatory genes (TNF-AIP3, STAT4, IL2RB) ~5% risk
Describe the role of HLA-DRB1/DR4 in the pathogenesis of RA.
HLA-DR4 selectively binds and presents antigen (arthritogenic peptide) to T cells, results in selection of autoreactive T cells in thymus
Describe the autoimmune nature of RA, including the role of antibodies, T cell cytokines, and MP/fibroblast cytokines.
Autoabs may include RF, ACPA which may attack joint antigens like type 2 collagen, or systemic antigens like glucose phosphate isomerase. These Abs contribute to synovitis by local complement activation.
T cell cytokines including IFN-gamma and IL-17 are present in low levels in RA synovium. T cells can contribute to synovial inflammation via antigen- independent mechanisms such as direct cell-cell contact with macrophages.
Macrophage and fibroblast cytokines are abundant in RA synovium. These include TNF, IL-1, IL-6, IL-8, IL-15, IL-18, GM-CSF, and IL-33 which serve to recruit inflammatory cells to the joint.
RA classically involves which joints?
Most characteristic is WRIST and PROXIMAL HAND followed by:
Shoulder
Elbow
Hip
Knee
* joint involvement tends to be symmetrical
Describe catastrophic antiphospholipid syndrome.
Multiple thromboses of medium and small arteries occurring over several days
What distinguishes drug induced Lupus from SLE?
No nephritis usually seen in Drug induced lupus.
Describe the histological manifestation of SLE in the skin.
Superficial and deep perivascular inflammation and mucin in the reticular dermis. Also seen is edema. Vasculitis with fibrinoid necrosis may also be present.
Describe the immunofluorescent manifestations of SLE in the skin.
Shows deposition of immunoglobulin and complement along the dermoepidermal junction. This is not diagnostic of SLE, and is also found in scleroderma and dermatomyositis.
You see moderate lupus on a kidney biopsy. What do you see that tells you it is lupus?
Wire-loop thickening of glomerular capillaries.
Describe the immunofluorescent pattern of lupus nephritis.
IgG deposits in a granular pattern
Describe the earliest pathological changes in Systemic Sclerosis, which also persist throughout the disease.
changes in endothelial cell function with increased apoptosis, upregulation of MHC class II and ICAM-1 expression on endothelial cells.
Describe a serious GI complication of SSc.
Gut dismotility* and telangectasias. Upper GI dysmotility more common. Lower dysmotility has bad prognosis.
*Collagen replacement of vascular and enteric smooth muscle results in hypomotility, lumen dilatation, tensile rigidity and eventual loss of organ functions.
What two conditions contribute to the majority of deaths in SSc?
Interstitial lung disease and PAH together account for 60% of mortality in pts with SSc.
Describe linear scleroderma.
Linear scleroderma is a limited cutaneous manifestation of SSc (not systemic). that presents as a linear streak that crosses dermatomes and is associated with atrophy of muscle, underlying bone and rarely the brain called “ en coup de sabre”.
Mixed connective tissue disease is most commonly associated with antibodies to:
U1-RNP
In general, this Ab predicts lack of severe CNS and renal involvement.
The absence of this condition, highly typical of MCTD, would suggest the need to consider another Dx.
Raynaud’s phenomenon
25% of MCTD pts develop this type of renal involvement:
Membranous glomerulopathy
Proliferative glomerulonephritis is uncommon in MCTD.
Describe the commonest CNS problems seen in MCTD.
trigeminal neuralgia & sensorineural hearing loss
What is the commonest cause of death in MCTD pts?
PAH
Describe the histology of SSc.
**Dead giveaway: Loss of Dermal-epidermal papillary projections (rete pegs). Dermal-epidermal interface is a straight line. This is due to underlying excessive deposition of collagen, deep fibrosis, and perivascular lymphohistiocytic infiltration. Also, loss of hair follicles and glands.
Describe the histological appearance of a renal glomerulus in SSc.
Shrunken, lacking inflammatory cells or proliferative changes. Also seen histologically will be interstitial fibrosis presenting as increases spacing between renal tubules in transverse section.
Describe the clinical hallmarks of Sjogren’s syndrome (SS).
xerostomia, keratoconjunctivitis sicca, and parotid gland swelling.
What Abs are we going to test for when Dxing Sjogren’s?
serum ANAs including: anti-Ro/SS-A and anti-La/SS-B
Autoimmune diseases are characteristically found more commonly in men or women?
Women.
Sjogren’s syndrome (SS) carries a 44-fold risk of acquisition of this malignancy:
Non-Hodgkin’s Lymphoma, MALT lymphomas
Risk factors for NHL include:
length of time with disease, low C4, type II cryoglobulins, anemia, lymphocytopenia, hypergammaglobulinemia, cutaneous vasculitis (palpable purpura), lymphadenopathy, splenomegaly, parotid gland enlargement, & peripheral neuropathy.
How does SS present renaly?
Infrequently: tubular interstitial nephritis, type I renal tubular acidosis, glomerulonephritis, and nephrogenic diabetes insipidus.
1/3 of pts with Sjogren’s experience this GI symptom:
esophageal dysmotility,
SS mimics this neurological disease on presentation:
multiple sclerosis
Describe the pulmonary manifestations of SS.
Xerotrachea, xerobronchitis, nonspecific interstitial pneumonitis, lymphocytic interstitial pneumonitis, usual interstitial pneumonitis, bronchiolitis, & lymphoma.
Describe the laboratory findings (Ab screen) or SS.
75-95% (+) for rheumatoid factor
85% (+) for ANAs
1/3-1/2 (+) for anti-Rho/SS-A and anti-La/SS-B
5-10% have low blood levels of C3 & C4
5-15% have leukopenia or thrombocytopenia
5-10% with primary SS have Type II or III cryoglobulinemia or monoclonal gammopathy
Describe the two types of SS.
Primary:
Chronic autoimmune inflammatory disorder
Lymphocytic infiltration and proliferation
destroys exocrine glands
Infiltrates other organs to a variable extent
Malignant transformation possible
Secondary:
A complication of another autoimmune connective tissue disease
Commonly seen in SLE and RA
Describe the histopathology or SS.
mononuclear inflammatory infiltrates, interstitial fibrosis. Clusters of lymphocytes.
Is rheumatoid factor present in the spondyloarthropathies?
No, rheumatoid factor is ABSENT in the “seronegative” spondyloarthropathies
Describe the HLA haplotype association found in spondyloarthropathies.
HLA-B27 very commonly found in pts w/ spondyloarthropathies. It is an MHC class I molecule that binds antigenic peptides and presents them to CD8+ T cells.
Is arthritis of the spondyloarthropathies found predominantly in the upper or lower extremities?
Lower
Describe the frequency of HLA-B27 in pts with ankylosing spondylitis compared to the general population.
Pts with AS: 90% have HLA-B27
Gen Pop: 8% have HLA-B27
Describe the epidemiology of Ankylosing Spondylitis.
Age: adolescence - 35 yo
Sex: 3x likelihood in males
Describe the pathology of ankylosing spondylitis.
Inflammatory cell infiltrate
Synovial inflammation similar to RA
TNF-a excess- pts respond well to humira (adalimumab)
Unknown cause.
Describe the clinical features of ankylosing spondylitis.
Insidious onset
Chronic low back pain/stiffness
Symptoms are worse in morning and improve w/ exercise
Symptoms gradually ascend up the spine
Describe the extra-articular features of ankylosing spondylitis.
Anterior uveitis 25-30%
Cardiac: aortic regurg, heart block, pericarditis, MI
Pulm: apical lung fibrosis, thoracic cage restriction due to ankylosis of costovertebral joints
Describe the “classic triad” associated with reactive arthritis.
Arthritis, urethritis, conjunctivitis. Triad not always complete.
Reactive arthritis is an inflammatory arthritis following an infectious process
What are the 4 organisms classically associated with Reactive Arthritis?
Chlamydia, Salmonella, shigella, C. difficile
Describe the epidemiology of reactive arthritis.
Uncommon (3-5/100,000)
Mostly males
75% HLA-B27 (+)
ReA more common in HIV/AIDS- more severe, resistant to therapy
Describe the clinical features of reactive arthritis.
Asymmetric oligoarthritis
Dactylitis
Axial disease: sacroiliitis and spondylitis
Enthesitis (inflamm of tendon-bone interface) —pathognomonic for reactive arthritis (Reiter’s)
Uretritis
Oral ulcers
Conjunctivitis
circinate balanitis- shit builds up around glans of penis
Describe the laboratory findings of reactive arthritis.
Inflammatory markers (ESR, CRP)
Culture is usually negative
Consider HIV
HLA-B27
Arthritis mutilans and “sausage fingers” are condition characteristics of:
Psoriatic arthritis. Digits contract and “telescope” because bones are being chewed up by the arthritis.
What feature of psoriatic arthritis helps distinguish it from RA?
increased vascularity and the presence of neutrophils in synovial tissues in psoriatic arthritis.
Describe the immunopathology found in psoriatic arthritis.
Elevated plasma levels of immunoglobulins
T cells express: HLA-DR, receptors for IL-2 and adhesion molecules. T cells secrete IL-6 and other proinflammatory cytokines.
Fibroblasts from skin and synovium proliferate and secrete IL-1 beta, IL-6, and PDGF.
This is all similar to RA
However, more TNF-a, IL-1B, IL-2, IL-10, and IFN-g
No pannus like in RA, but high vascularity
Also increased levels of IL-18 that contributes to angiogenesis and mononuclear cell recruitment.
Describe tx of psoriatic arthritis.
Infliximab or adalimumab
Describe the pathophysiology of enteropathic arthritis.
Gut wall is leaky to microbes. Microbes get into circulation, and interact with lymphocytes, cause autoimmunity via molecular mimicry and damaging circulating immune complexes.
Inflammatory arthritis is associated with these 3 inflammatory gut pathologies.
Crohn’s Disease
Ulcerative colitis
Whipple’s disease (rare)
Usually occurs after onset of GI disease, but can occur before
Describe the genetic haplotypes found in individuals with celiac disease.
HLA-DQ2 & HLA-DQ8
Describe the common symptoms of pts with celiac disease.
Diarrhea, IBS, fatigue, headache, arthralgias. Also seen, less commonly: Type I diabetes, anemia, osteoporosis, neuropathies, and joint symptoms.
How do you Dx celiac disease? What is Tx?
Small bowel biopsy, presence of serum IgA antitissue transglutaninase, and IgA antiedomysial abs.
Tx: gluten free diet.
Bonus: there is an association (10% of IgA deficients) between celiac disease and selective IgA deficiency.
What is rheumatoid factor?
An IgM ab against IgG
MTX is a primary tx modality for RA. List its major complications.
Pulm interstitial fibrosis
macrocytic anema with hypersegmented neutrophils
Which Ab has 100% specificity for Lupus?
Anti-Sm
A pt has anti-dsDNA. They have lupus (more than likely) and what other pathological condition?
Nephritis
A negative side effect of this class of drugs used in the treatment of RA is a lupus-like syndrome and also can produce a lab result showing dsDNA.
Anti-TNF-a mabs
Methotrexate is thought to accelerate the formation of this pathological feature of advanced RA.
subcutaneous nodules of pallisading histiocytes. Usually present as non-tender, moveable bumps on the elbow or just distal to it along the ulna.
Clinicians are reluctant to make a Dx of SLE without this antibody titer being positive:
ANA is highly sensitive for SLE but not very specific. Pt doesn’t have (+) ANA titer, prob doesn’t have Lupus.
In a pt w/ systemic sclerosis, a prolonged rise in BP from their baseline would suggest:
Renal capillary pathology (hypertensive renal crisis) necessitating starting the pt on ACE-Is.
Which Ab is found in Systemic Sclerosis (SSc) that is associated with hypertensive renal crisis, a complication of SS?
Anti RNA polymerase-3
Which Ab is found in Systemic Sclerosis (SSc) that is associated with limited cutaneous disease, a complication of SS?
Anti centromere ab
Which Ab is found in Systemic Sclerosis (SSc) that is associated with pts with antisynthetase syndrome, a subset of the inflammatory myopathies associated with SS?
Anti Jo1
This Ab is found in a subset of systemic sclerosis pts suffering from dermatomyositis
Anti Mi-2
This Ab is associated with diffuse scleroderma and the presence of interstitial lung disease.
Anti SCL-70
The Dx of Sjogren’s Syndrome lies in these 3 general tests:
serologic (anti-SSA, anti-SSB, ANA, RF)
ophthalmologic (schirmer test)
oral signs (labial salivary gland biopsy)
What is the most common pulmonary manifestation seen in Sjogren’s Syndrome?
Nonspecific interstitial pneumonia (NSIP)
Remember, PAH, is seen in SSc and MCTD, but it’s occurrence in SS is rare.
