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Diagnosing Autoimmune Conditions
Test Review
81
Biology
Professional
02/02/2012

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Cards

Term
A patient presents with severe opportunistic infections and evidence of liver disease.

The patient's blood work comes back and you notice that they are CD40L deficient.

What is going on?
Definition
This is Hyper IgM syndrome (HIGM1)

Without CD40L on T-cells, co-stimulation and B cell class switching cannot occur.

You end up with a lot of IgM, and low IgA, IgG and IgE

The only option is really bone marrow Tx
Term
How would you treat patients with HIGM1 and HIGM3 differently
Definition
HIGM1 is CD40L (T cells) and requires bone marrow tx

HIGM3 is CD40 (B cells) and can usually be treated with IVIG and prophylactic antibiotics
Term
A 4 month old boy presents with absent lymph nodes, tonsils and adenoids. He had been fine for the first 2 months of life and his 2 sisters are normal.

The blood work comes back and you observe lymphopenia (B cell).

You run a BTK PCR test and discover that it is deficient.

What is going on and how do you treat?
Definition
This is X-linked Agammablogulinemia (B cell disorder).

Without Bruton's tyrosine Kinase prevents B-cell maturation.

He had been fine because of maternal IgG passage across the placenta

Treat with IVIG and prophylactic antibiotics
Term
A 30 year old man presents with vascular anomalies, bone fragility, hyperextensibility and persistent primary teeth.

He also has a mild pnemonia and a number of skin rashes.

What might you look for?
Definition
These are classic features of AD-HIES.

You would want to measure IgE (look for elevation) and do molecular experiments to look for STAT 3 mutations (too much IL-17 response and too little IgE is characteristic)
Term
A 60 year old male patient presents with recurrent respiratory tract infections.

The blood work comes back and you notice B-cell lymphopenia.

What is your diagnosis and how will you treat?
Definition
CVID and XLA should be on differential.

Given that the patient is older, it is probably more likely CVID than XLA

Treat with IVIG and watch for cancer.
Term
An older patient presents with recurrent infections and allergic responses (ATOPY). They are confused because they have never had any of these symptoms earlier in life.

The blood work comes back, and there is hardly any IgA.

What is your diagnose and how do you treat?
Definition
XLA, CVID and selective IgA could be on differential.

However, given that the Ig deficiency is specific to IgA, this is selective IgA deficiency (1:700- very common!)

They might not have seen it before because it is clinically silent in 2/3 people.

Treat with prophylactic antibiotics and monitor for CVID.
Term
A patient presents with recurrent Staph aureus and Serratia infections, as well as granulomatous inflammation (colitis and gastric outlet obstruction).

What tests might you order?

If you are right, how might you treat?
Definition
You probably suspect CGD given the granulomatous inflammation and opportunistic infections.

You could

1) Perform dihydrorhodamine oxidation assay with Flow cytometry to look for NADPH Oxidase issue

2) Gene analysis for NADPH oxidase mutations (especially in X-linked gp91phox)

3) Treat with Bactrim and Itraconazole, or possibly with a bone marrow transplant.
Term
A patient presents with Omphalitis impaired wound healing and severe periodontitis. You discover that they had had delayed separation of the umbilical chord.

Their blood work comes back and you see evidence of leukocytosis. Upon further testing, you discover CD18 mutations.

What is going on?
Definition
LAD-1 (delayed separation of umbilical chord and omphalitis)

CD-18 is important for leukocyte adhesion to endothelial cells for transmigration.

You basically can't get an immune response to infection and injury.

2) Treat with prophylactic antibiotics and maybe BMT.
Term
A patient presents with Omphalitis impaired wound healing and severe periodontitis. You discover that they had had delayed separation of the umbilical chord.

Their blood work comes back and you see evidence of leukocytosis. Upon further testing, you discover mutations in a GDP-fucose transporter.

What is going on and how do you treat?
Definition
1) LAD-2 (LAD-1 is CD18) where defect in fucosylation prevents E selectin ligand binding and disables leukocyte rolling.

2) Treat with prophylactic antibiotics and supplement with fucose.
Term
A young child presents with partial albinism and gild lysosomes in their blood.

Their patients were inbred.

Whats going on? How can you treat?
Definition
RARE- Chediak Higashi (Secretory Granule Disorder)

1) Defect in LYST leads to impaired lysosomal trafficking.

2) You have increased succeptibility to bacterial infections and you NEED A BONE MARROW TX
Term
Which immune deficiencies are B-cell related?
Definition
XLA, HIGM1/HIGM2, CVID, ADHEIS, selective IgA
Term
Which immune deficiencies are Phagocyte-cell related?
Definition
1) Chediak Higashi (lysosomal trafficking)

2) CGD

3) LAD1/LAD2
Term
A young child presents with Tetralogy of Fallot. Their blood work comes back and indicates hypocalcemia and T-cell lymphopenia. They also have short palpebral fissures.

What test should you run, and if you are right, how can you treat?
Definition
Look for 22q11.2, because this sounds like DiGeorge, with Cardiac, parathyroid, Thymus and Facial dysmorphia issues.

Remember, cardinal features are

1) Thymic hypoplasia

2) Cardiac invovlement

3) Fascial dysmorphism

4) Parathyroid issues

Treat with a Thymic transplant if you can, and with calcium supplementation and prophylactic antibiotics
Term
What is the only immunodeficiency that is traditionally treated with a thymic transplant?
Definition
DiGeorge presents with severe thymic hypoplasia.
Term
A young girl presents with a number of viral infections and chronic upper respiratory disease. She has no opportunistic infections though.

What is your differential and what tests do you want to run?
Definition
Bare Lymphocyte Syndrome I, Digeorge, SCID, ATX

Given that there are no opportunistic infections, BLS1 might be more likely, since CD4 T-cells are competent.

Look for lack of MHC1 expression in TAP-1/TAP-2 for evidence of a disrupted endogenous pathway of antigen presentation for CD8+ T cell activation.

Without CTLs, you cant fight off viral infections.
Term
A 2 month old girl presents with chronic diarrhea and opportunistic infections.

Her blood work comes back and her TRECS test is normal. Her T cell count is low but not absent.

What is going on?
Definition
Sounds like SCID, but TRECS is normal and a few T cells can be found.

It is a shot in the dark, but if MHC II expression is mucked up (BLS2), she might have defective CD4+ T cells
Term
A 2 month old presents with an absent T-cell count, but normal B and NK cell counts.

What cytokines might be implicated in this type of SCID?
Definition
T cell specific so

1) IL-7R-y

2) IL-2R

3) CD3
Term
A 2 month old presents with an absent T and B cell counts but normal NK cell counts.

What cytokines might be implicated in this type of SCID?
Definition
1) RAG1, RAG2 (cleavage in TCR/BCR somatic recombination in bone marrow and thymus)

2) Argemis/Cernunnos (repaire in somatic recombination)
Term
A 2 month old presents with an absent T and NK cell counts but normal B cell counts.

What cytokines might be implicated in this type of SCID?
Definition
50% of patients with SCID have this common gamma chain mutation.

It is used by cytokines that lead to development of NK and T cells (IL-2, IL-9, IL-15 and IL-7).
Term
A 2 month old presents with an absent T/B/NK cells, as well as skeltal findings and hearing loss.

What cytokines might be implicated in this type of SCID?
Definition
Look for ADA issues.

ADA is important for purine salvage pathway (problems decrease DNA synthesis/repair in lymphocytes increase toxic intermediates)
Term
A 2 month old patient presents oral candidiasis, chronic diarrhea, opportunistic infections and dermatidis.

What is your diagnosis? How do you treat?
Definition
Looks like SCID (normally X-linked), but do a TRECS test to be sure (circular DNA from TCR rearrangement)

BMT as soon as possible!
Term
A young boy presents with no eyebrows and erythroderma. You notice a normal WBC count.

What is going on?
Definition
Looks like SCID, but normal WBC count indicates otherwise.

Probably Ommen Syndrome, where Oligoclonal T cells present as normal WBC count.
Term
A 3 year old young girl presents with petechia, bloody stool, eczema and a sinopulmonary infection.

What is going on?
Definition
Sounds like SCID, but they don't live to 3!

This is probably Wiskott-Aldrich

X-linked WASP issue causing T:B cell interaction issues as well as megakaryocyte problems.
Term
A young boy presents with an abnormal gait and red-stripes in the sclera of his eye. He is very photosensitive.

The blood work comes back and you see elevated AFP.

What are you thinking?
Definition
Ataxia-Telangiectasia

The gait/AFP and radiation sensitivity are very characteristic.
Term
A 30 year old man presents with a history of smoking, crescentic glomerulonephritis and pulmonary hemorrhaging.

You discover that has the HLA-DR15 and DR4 genes.

What do you suspect the issue is and how might you confirm?
Definition
Could be Goodpasture's

Given the glomerulonephritis you might think SLE and the DR4 with the smoking makes you think RA, but the isolated renal and pulmonary issues point to Goodpasture's.

To make sure, check for anti-GBM antibodies, which attack type IV collagen in the lungs and kidneys.

Also look for an even deposition of anti-GBM in immunoflourescence.
Term
A 40 year old woman presents with exertional dyspnea, fatigue and pallor.

She is suffering from an EBV infection and also has adenocarcinoma.

Her blood work comes back with a positive direct Coomb's test and very low Hb.

What is your diagnosis?
Definition
Sounds like the Warm Agglutiins (IgG) version of autoimmune hemoyltic anemia (type II reaction), which tends to present with malignancies and viral infections.

The positive direct Coomb's test identified antibodies binding to antibodies on RBCs, suggesting an autoimmune attack of IgG-RBCs.
Term
A 50 year old man presents with exertional dyspnea, fatigue and pallor that gets worse with cold exposure

He is suffering from an EBV infection as well.

His blood work comes back with a positive test for the mAb 9G4.

After 2 weeks, the symptoms have gone away, despite no particular treatment.

What is your diagnosis?
Definition
Cold Agglutinins (IgM) Autoimmune hemolytic anemia.

The symptoms fit and 9G4 is specific for V(H)4-34, which is on RBCs and is important for complement-mediated destruction.

The fact that it disappeared on its own supports the notion that it was Cold Agglutinins, which is IgM-mediated.
Term
A 56 year old man presents with recurrent episodes of angioedema and severe swelling. His BP is 90/65.

You take a history, and he tells you he has been very stressed at work.

His blood work comes back and you notices high Bradykin levels.

What is going on?
Definition
Acquired angioedema (anti-C1 INH) (blocking or type 4 reaction)

The high Bradykin is causing vasodilation and the low BP. It is raised because of autoantibodies against the C1-INH protein.

The anti-C1-INH antibodies are probably around causing an overactive complement response, which might have arisen because of overactive Kinin cascade.
Term
A 45 year old woman presents with ocular, bulbar and limb muscle weakness.

She performs abnormally on the Tensilon test (gets stronger).

What is your diagnosis and how might you treat?
Definition
Myasthenia Gravis (Type II or blocking)

The "total" muscle weakness indicates MG over Myosities (which should be peripherally restricted) and the abnormal tensilon test is a cue that her AcH system is not working appropriately.

Remember, MG can take 2 forms: AChR (blocking) and MuSK (type II), each involved in AChR signaling.

When you added inhibitor of AChR in the Tensilon test, most patients get weaker, but she gets stronger, which is a clue.

MG is associated with thymic hyperplasia, so a thymectomy may help (the only other disease we learned that involves this treatment is DiGeorge immunodeficiency).
Term
A patient presents with hypocalcemia, dry skin and fatigue.

Their blood work comes back and you notice high levels of anti-thyroid peroxidase enzyme.

What is your diagnosis?
Definition
Hashimoto's thyroiditis (blocking reaction)

There is Goitrous and Atrophic staging, which the later being associated with hypothyroidism causes by autoantibody attack of thyroid peroxidase.

T-cells have also infiltrated the thyroid, so you might give immunosuppressives?
Term
A patient presents with hyperthyroidism, goiter, orbitopathy between the eyelids and lens, and localized myxedema (swelling below legs).

What do you suspect the issue is?
Definition
Grave's disease is the only disease we learned about that presents with hyperthyroidism.

Activating autoantibodies against thyrotopin (TSH) receptor are causing thyroid hormone synthesis and thyroid growth (Goiter)
Term
A 14 year old boy presents with bullous skin lesions, dermal-epidermal skin blisters, and both mucous membrane and skin involvement.

What test would you run to confirm your diagnosis?
Definition
Sounds like Pemhigus vulgaris (type II reaction) with both skin and membranous involvement.

You would want to look for anti-dsg1 (skin) and anti-dsg3 (mucous membrane).

These autoantibodies are causing steric hindrance, complement activation and disrupted intracellular signaling.
Term
What disease would you be concerned of a patient getting who is (+) for HLA-B27?
Definition
Inflammatory Spondyloarthropathies.

Specifically, Ankylosing and Reactive forms.
Term
What disease would you be concerned of a patient getting who is (+) for HLA-B4?
Definition
Rheumatoid Arthritis.

You would look for anti-CPP antibodies and a history of smoking as well.
Term
A 25 year old women presents with pain and minimal swelling in her PIP joints. She is experiencing arthralgias and chest pain.

Her urine analysis comes back with high protein content and you notice a few ulcers in her nose.

What are you thinking and how might you confirm?
Definition
This sounds like SLE.

The fact that she is a young woman (prevalence is 9:1 female to male at ages 15-35) is a hint and she expresses 4 of the Diagnostic criteria (ulcers, serositis, arthritis and renal).

You could check her blood for anemia and anti-dsDNA antibodies. You could also find out about photosensitivity and rashes, or immunological involvement.
Term
A young woman presents with chest pain and joint sensitivity.

You run some blood work and discover homogenous staining on an ANA.

What might you ask about in relation to her history?
Definition
You sometimes see this staining in drug-induced Lupus. Given her symptoms (you still need more, of course), it is reasonable to ask about drug use or just medication use.
Term
A 50 year old woman presents with fibrous skin and serositis and pulmonary hypertension. She also has inflammation in her esophagus.

Her blood work comes back and you notice an anti-centromeric ANA. What are you thinking?
Definition
She is presenting with classic symptoms of schleroderma and the centromeric stain along with the hypertension is suggestive of limited systemic schleroderma.

I
Term
A patient presents with a (+) ANA with a speckled appearance.

What is on your differential? How could you find out more?
Definition
1) Sjogren's

look at ocular symptoms (dry eye), oral dryness, ocular signs (Schirmer's/Rose-Bengal), Histopathology (lymphoid foci meaning germinal centers), Salivary gland involvement (parotid sialography orscintography).

2) Neonatal lupus

Look for 4 Skin RASH NIA

In blood, look for low complement, elevated ESR, anti-dsDNA. Also look for proteinuria in urine.
Term
You determine a patient has SLE. What treatment options are available to you?
Definition
1) Belimumab- human monoclonal antibody against BAFF (prevent the survival and propagation of B cells producing autoantibodies

2) Hyroxychloriquine- MHC-II expression

3) Rituximab- Chimeric monoclonal antibody against CD20 on B-cells (depleting agent).

4) Anti-TNF therapies
- Etanercept (soluble TNF fusion protein)
- Infliximab (chimeric mAb against TNF)
- Adalimumab and Golimumab (human mAb against TNF)
- Certolizumab (PEGylated mAb for increased half life)
Term
A patient presents with a (-) ANA for dsDNA and Sm. How certain can you be that they do not have SLE? What about a normal C1q?
Definition
Not very. Remember, these are SPECIFIC but not sensitive.

C1q is found in 90%, so a negative would be more informative
Term
A 63 year old woman presents with hyperparathyroidism and episodes of acute arthritis in the knees, wrists and elbows.

What do you think is going on and how might you confirm?
Definition
You should immediately think about Gout, RA, Pseudogout and Spondyloarthropathy.

There is no spine involvement making SA unlikely.

The elbow/knee distribution is also not characteristic of Gout, which usually is in the hand and forefoot/ankle (also you rarely see gout in women).

If this was RA, you would most likely see symmetric, polyarthritis, with nodules. To be more sure, look for anti-CCP, RF and smoking.

It looks like Pseudogout, but to be sure, you should look for rhomboid-shaped, positively birefringent crystals composed of calcium pyrophosphate.

On X-ray, you should see fluffy white radioopaque deposits between joints.
Term
How would you treat a patient for CPPD?
Definition
NSAIDS, Corticosteroids, Colchicine (fore flares)
Term
A 50 yera old man presents with a uric acid level of 8.5mg/dL. He is hypertensive, overweight, and has severe pain in his MTP joint. You also notice tophi and olecranon bursitis.

What are you thinking and how might you confirm? How would you treat?
Definition
This sounds like Gout.

The uric acid level, along with the obesity and hypertension are pathoneumonic.

You should look for radioluscent, parallel uric acid crystals that are negatively birefringent.

If the Gout is acute, treat with NSAIDS, cochicine , corticosteroids and IL-1 antagonists (anakhinra). In cases of nephrotoxicity, avoid NSAIDS and steroids.

If chronic, you can treat with Allopurinol (hypoxanthine to xanthine) and Febuxostat (xanthine to uric acid).

If there are no Renal issues, y could also use Uricosurics like Probenecid and Benzbromarone to inhibit UA uptake).

You could try Pegloticase to breakdown UA into Allantoin.

You could also try colchicine for flares (stop NALP3 from acting with caspase-1 to cleave pro-IL-1b and cause inflammation)
Term
A patient presents with Gout and you want to give them Cochicine. What 6 things are you trying to prevent?
Definition
Colchicine blocks NALP3 from working with caspase-1 to cleave IL-1b. So you are trying to stop IL-1.

IL-1 does 6 things in the joints.

1) Induces COX for prostaglandin
2) activates HSP
3) Release of TNF
4) Liver to make acute phase (CRP)
5) Increase blood PMN
6) Fever
Term
A 50 year old white male presents with vasculitis in the upper/lower respiratory tracts, granulomatous infection and renal proteinuria.

He has otitis media and a perforated septum as well.


What is going on and how could you treat?
Definition
Sounds like GPA (Wegener's)- make sure it is not an infection.

This is the classic triad of symptoms and the patient is Caucasian.

Since he has the triad, you could also look for c-ANCA (patients with the disease are 90% likely to have the triad with c-ANCA)

You could try Steroids or steroid-sparing immunosuppressents (MTX, sulfalazone, leflunomide, rituximab, mycophenolate mofetil, ect), but there are COMPLICATIONS.
Term
What is the basic idea of GPA pathogenesis?
Definition
1) Insult activates PMNs to express PR3

2) PR3 signals to DCs, which go to LN and activate CD4+ T cells with IL-18 to become Th1 cells.

3) They release IFN-y and acute phase reactants, and cause B-cells to differentiate into plasma cells that release ANCA.

4) ANCA enters vessels, bind to PR3 and promotes PMN recruitment and inflammation.

5) Antibody-antigen immune complexes can deposit in kidney, causing renal failure, as well as in the respiratory tract.
Term
A 54 year old woman presents with dry eyes and dry mouth, as well as parotid gland swelling.

You suspect Sjogren's, but are unsure. How do you confirm and how might you treat?
Definition
Need 4 of 6 with either 4 or 6, or 3 of 4 quantitative criteria.

1) Ocular symptoms (sandy feeling)

2) Oral dryness

3) Ocular signs (Schirmer and Rose-Bengal)

4) Histopathology (look for germinal centers in salivary biopsy)

5) Salivary involvement (sialography, scintography)

6) SSA/SSB

Treat Xerostomia with oral secretion replacement, stimulation of salivary flow (Pilocarpine and Cevimelene), anti fungals and biotene tooth paste for dental carries.

Treat Keratoconjuctivitis with replacement tears, Cyclosporine/Tacrolimus for inflammation, or Punctal occlusion.

Treat Glandular symptoms with immunosuppressives (hydrocholoroquine, rituximab,) and Extraglandular with everything BUT TNF
Term
What extra-glandular symptoms should you look for in diagnosing a case of Sjogren's?
Definition
Symmetric Involvement

1) Skin involvement (Raynaud's)

2) Renal (interstitial nephritis)

3) Joints (arthalgias/arthritis)

4) Nerve (peripheral neuropathy)

5) Lungs- interesitial lung disease

6) Fatigue (worst around)
Term
What should you monitor a patient with primary Sjogren's for? Why?
Definition
Lymphoma tends to develop! Also, Candidacidal activity of saliva.

Remember, epithelia serve as APC for T cells, which let out CXCL13 to recruit B cells, which produce BAFF and SSA/B, which leads to inflammation.

Overactivity of B cells (BAFF release and autoantibodies) and germinal center formation can lead to B-cell cancer down the line.

Also, anti SSA/SSB act on TLRs to increase IFN-a and activate myeloid DCs

For Candida, there is an absence of defensins and histatins (usually produced by IL-17 cells when APCs release IL-6, TGF-b and IL-23) in saliva to fight off Candida.
Term
A 54 year old woman presents with fibrosis of the skin in her distal extremities, and hypertension. What is your diagnosis?
Definition
Fibrosis of skin is classic scleroderma, and hypertension is usually seen in the Limited form.

You might look for anti-centromeric and anti Th/To antibodies.

Your Sclerosis, you need immunologic, fibroblast and vascular involvement

Candidate genes include STAT 4 (Th1 (+) and Th2 (-)), IRF5 (interferon regulatory factor) and HLA-DR5
Term
A 56 year old woman presents with Raunaud's, fibrosis of the skin, congestive HF, pulmonary fibrosis and is in renal crisis.

What is your diagnosis and how can you confirm?
Definition
Fibrosis of skin is classic systemic scleroderma, and these other factors suggest the Diffuse form.

You should look for collagen deposition on biopsy and capillaries on nailfold microscopy to look for Raynaud's.

You might look for anti-SCL70, anti RNA Poli III and anti-U3RNP antibodies.

For Sclerosis, you need immunologic, fibroblast and vascular involvement

Candidate genes include STAT 4 (Th1 (+) and Th2 (-)), IRF5 (interferon regulatory factor) and HLA-DR5
Term
What is the basic pathogenesis of SSc?
Definition
Diffuse presents with early visceral involvement, while Limited presents with late visceral response.

1) Endothelial injury leads to dysfunction through overactivity of Endothelin, which contracts vessels and recruits fibroblasts to lay down collagen.

There is defective vasculogenesis because of a lack of EPCs and EC activation leads to inflammation.

2) Endothelial cells act as APCs that present antigens to CD4+ T cells (Th2 dominant response) leading to Mast cell/eosinophil activity, B cell activation and autoantibody production. Autoantibodies are not known to be pathogenic, except SCL-7 is thought to bind to fibroblasts, perhaps activating them.
Term
A 45 year old woman presents with symetric arthritis of the hands, wrists and feet, with strange nodules.

What is on your differential and how would you test to confirm?
Definition
RA, Spondyloarthropathy, Gout, Pseudogout.

SA would have back involvement and asymetric arthritis, Gout you would see uric acid increase and Pseudogout would have positively birefringent calcium PP crystals.

For RA, you see this symetric, polyarthritic involvement with wrist/feet/hands distribution, probably with morning stiffness.

You could look at RF (high sensitivity) and anti-CCP (high specificity), as well as smoking history.

You can classify according to joint involvement, duration, acute phase reactants (CRP/ESR) and Serology
Term
What is the cause of 50% of excess mortality in RA
Definition
premature CVD!
Term
What is the basic pathology of RA?
Definition
Remember, the hallmark in Pannus formation.

Pannus forms with neovascularization, inflammatory cell infiltration, and pro-inflammatory cytokine-mediated vascular activation


1) The leading edge of pannus (type A and B synnoviocytes, PCs expressing RF) crosses from fibrocartilage into bone as Type B synnoviocytes release MMPs

2) Inflammation and destruction of joints occurs because APC presentation to TCR leads to cytokine release that ultimately causes pain and disrupts mobility.

Role of autoantibodies is unclear

RF binds to Fc region of IgG and may regulate complement deposition.

anti-CCP binds to citrulinated peptides (post translational modification as PADI deaminates arginine on peptides)
Term
How would you go about treating a diagnosed case of RA?
Definition
1) Start with prednisone (bridge therapy) and add MTX (or maybe salfalasone or Leflunomide/very long half life)
If case is mild, may use Hydroxycholoquine (anti-malarial)

2) Gradually get off steroids and keep MTX high.

3) If MTX fails, try anti-TNF therapies

Etanercept (fusion soluble receptor)
Infliximab (chimeric)- generally given with MTX
Adalimumab (humanized)
Golimumab (fully human)
Certolizumab (Pegylated)

4) If during pregnancy and symptoms don't improve, you need to avoid DMARDs and Anti-TNF, and can give steroids.

5) Could try anti-IL1 (anakinra is recombinant IL-1R) or IL-6 (Tociluzumab)
Term
What is the most common chief complaint of patients with RA?
Definition
Fatigue.
Term
What are the 4 mechanisms of action of Rituximab and when should you prescribe it?
Definition
1) Autoantibody depletion
2) Diminished cytokine release and co-stimulation
3) Diminished antigen presentation
4) CD20+ depletion

Give in RA if TNF fails
Wegener's
CLL

Be careful of PML
Term
When should you prescribe Natalizumab and how does it work?
Definition
For MS or IBD, but be careful of PML (also the case with Efalizumab-CD11a)!

It is a cell-adhesion inhibitor (humanized mAB) that binds alpha-4 integrin.

In IBD, alpha-4 integrin binds beta-7 integrin to allow lymphocytes educated in the GALT to leave and enter gut tissues (want to prevent inflammation)

In MS, alpha-4 integrin binds beta-1 integrin, which allows lymphocytes to act on the brain.
Term
You have a patient with RA. What test should you run before prescribing anti-TNF agents?
Definition
PPD test!

anti-TNF drugs may cause refractory TB, as well as rare opportunistic infections.
Term
Why might you want to treat RA with anti-IL-6 therapy?
Definition
IL-6 causes

1) induction of antibodies

2) activation of T cells

3) Induction of acute phase reactants

4) Maturation of megakaryocytes (platelet activation)

5) Activation of osteoclasts (bone resorption)
Term
Why might you give a patient with RA Abatacept, Ustekinumab or Denosumab?
Definition
Abatacept a fusion protein that is CTLA-4Ig, which should inactivate T-cells

Ustekinumab is a human anti IL-12/IL-23 agent that prevents CD4+ cells from going the Th1 route and making IFN-y.

Denosumab is a human antibody against rankL that prevents bone resorption.
Term
Why might you give an anti-JAK3 agent to people with RA?
Definition
JAK3 is important for common y-chain signaling (IL15, IL7, IL2, IL-4, ect).

You want to prevent lymphocyte activation
Term
A patient presents with with luekocytosis, a left shift, anemia and thrombocytopenia, as well a mutation in NOD2.

What do you suspect is going on?
Definition
These are features of IBD (especially NOD2). 30-40% of Chron's patients have NOD2 polymorphisms.

Remember, NOD2 and ATG16L1 are expressed by paneth cells in the gut, where they play a key role in the secretion of anti-microbial enyzmes and defensin proteins.

NOD2 signaling is part of the innate immune response to LPS through TLR4, which ultimately leads in IL1B activation through NF-kB.

ATG16L1 is important for autophagy and proper granule exocytosis.

W
Term
What is the basic pathology of IBD?
Definition
A decease in the innate immune system's ability to deal with foreign bacteria, causing growth of microorganisms that fuel aberrant secondary immune responses.

Lymphocytes are educated in Peyer's Patches of the GALT and then they leave (a-4:b-7 integrin mediated) to enter tissues, where they become Th1 cells that release IFN-y and TNF-a and Th17 cells.

1) TH1 cells release TNF-a
2) Th17 cells recruit PMNs
3) NOD2/ATG16 affect IL-1b signaling
4) IL-23 axis influence susceptibility
5) You see a switch from IgA to IgG, ASCA antibodies (Chron's) and P-ANCA (UC)
Term
What treatments are available for IBD?
Definition
1) Natalizumab- attacks the alpha-1 integrin to prevent lymphocyte migration from the GALT to the tissues.

2) Infliximab- chimeric antibody that attacks TNF
Adalimumab- humanized mAB against TNF

Enterecept DOESN"T WORK
Term
How might you determine if a patient has Chron's disease or UC?
Definition
1) Chron's involves "pathhy" inflammation that extends from mouth to anus. You are also more likely to see ASCA antibodies

2) UC involves colon only and you will likely see P-ANCA antibodies
Term
A patient presents with diarrhea, nausea, anemia and a family history of celiac disease.

How might you determine if they have the disease and how might you treat?
Definition
1) look at anti-glutaminase antibodies

2) Look for scalloping and villus blunting on biopsy

3) Do they have HLA-DQ2 and DQ-8 (95% sensitivity)

4) Treat by diet or Prednisone in refractory cases
Term
What is the basic pathogenesis of Celiac disease?
Definition
1) Epithelial barrier breakdown causes release of gliadin peptides into lamina proria

2) Gliadin peptides are resistant to cleavage because of Q and P

3) Gliadin binds really well to DRQ-2 and DRQ-8, and EVEN BETTER if transglutaminase has deaminated Q to E.

4) Inflammation is propagated by dysregulated adaptive signaling from CD4+ T cells, y/d T cells and B cells.
Term
A 27 year old woman presents with insidious-onset, inflammatory peripheral arthritis in 3 joints on her left side, with spinal involvement. They are also HLA-B27 (+), and show anterior uveitis, aortitis and psoriasis.

What is going on and how could you confirm/treat?
Definition
1) Sounds like an inflammatory spondylarthropathy.

The asymmetric inflammation and back involvement rule out RA, and the HLA-B27 is found in 95% of patients with AS (also suggesting of ReA). Also, the young age and Oligoarticular (<5 joints) is characteristic of SA.

Check to see if they are RF (-)

2) Treat with NSAIDS, Sulfasalzine or MTX (neither treat spine), and anti-TNF drugs such as adalimumab.

If it is IBD-associated, you could try a colectomy (only for US, not Chron's)
Term
What is the basic pathogenesis of AS? What features can indicate poor prognosis?
Definition
The idea (also called "Arthritogenic Peptide Hypothesis") is that arthritogenic peptides with arginine at position 2 bind to B27 pocket.

HLA-B27 AA sequences share common proteins with Yersinia and Shigella, and an autoimmune response can be generated (Molecular Mimicry)

People with HLA-B27 seem to be less able to clear infected macrophages.

Hip involvement, ESR>30, Oligoarthritis, onset <16 and Dactylitis are all associated with poor outcomes.

Remember # men= # women in Psoriasis form, but m>w otherwise.

Granulation tissue and inflammation are found at entheses
Term
You suspect a patient has Ankylosing Spondyloarthritis. What radiographic changes should you look for?
Definition
1) Enthesitis with Enthesophyte boney spurs

2) Sacroiliitis and Discitis

3) Osteoporosis with bone fractures.
Term
A 13 year old boy is having difficulty brushing his hair or walking because of muscle weakness. He has rashes over his MCP joints and interstitial lung disease.


You take a muscle biopsy and observe inflammatory infiltrate within the muscle fascicles (the myofibers themselves).

What is your diagnosis, how can you further confirm it and how could you treat?
Definition
This is Juvenile Polymyositis.

Look at anti-Jo-1 antibodies to be sure

It is polymyositis and not DM, because the myofibers are inflamed, and not the blood vessels.

Treat with NSAIDS
Term
What is the basic pathology of myositis?
Definition
1) Virally damaged muscle liberates autoantigenic aminoacyl-transfer RNA synthetases (such as Jo-1)

2) These enzymes are cleaved during apoptosis to monocyte activator and IL-8 like portions, which recruit mononuclear cells that induce innate and adaptive IR, which perpetuate myositis.

3) In DM, IFN-a and b genes are turned on (adaptive response), and IFN-inducible protein (MxA) can be detected.

** Selection of self-molcule (Jo-1 antigen) as target for autoantibody response may be consequence of pro-inflammatory properties of molecule itself**
Term
How can you tell between DM and PM?
Definition
1) DM is perivascular B cells and C5-C9 in blood vesels. Perivascular infiltrate is found around fascicles.

2) PM is lymphocyte attack of the myofiber, with inflammatory infiltrate WITHIN the fascicles.
Term
Explain how NSAID, GC, Zafirlukast and ZIleutin pharmacology relates to Arachidonic acid metabolism
Definition
Membrane-bound AA (ETA), EPA and dihomo-gamma-linoleic acid are cleaved and liberated by PLA, which can then be acted upon by COX-1 (constitutive), COX-2 (inducible) or 5'LOX.

- The COX route leads to prostaglandin, prostacyclin and thromboxane synthesis

- The 5-LOX route leads to Leukotriene B4 (LTB4) synthesis form 5HPETE and short-lived anaphylactic substances (LTC4/D4/E4) from LTA4 (GSH-mediated)

1) Glucocorticoids such as Lipocortin inhibit PLA (prevent AA liberation)

2) NSAIDs inhibit COX-I and II (prevent PGG2 formation)

3) Zileutin inhibits 5'-LOX (prevents 5HPETE formation)

4) The leukotriene receptor antagonist, Zafirlukast inhibits LTC4/D4/E4 (short-lived anaphylactic substances)
Term
Would you be more likely to give a patient with Asthma, TXA2, PGI2 or Leukotrienes?
Definition
PGI2 is the only vasodilator of smooth muscle

TXA2 and Leukotrienes constrict and would further close the airway.
Term
Would you be more likely to give a patient with Asthma, TXA2, PGI2 or Leukotrienes?
Definition
PGI2 is the only vasodilator of smooth muscle

TXA2 and Leukotrienes constrict and would further close the airway.
Term
Would you be more likely to give a patient with Asthma, TXA2, PGI2 or Leukotrienes?
Definition
PGI2 is the only vasodilator of smooth muscle

TXA2 and Leukotrienes constrict and would further close the airway.
Term
During a blood clot, which eicosanoids would be dominating?
Definition
TXA2 is a platelet aggregator while PGI2 is an anti-aggregate.

LTB4 is important for PMN migration
Term
What eiconsanoids are implicated in causing severe pain?
Definition
PGE2 and PGI2 (prostacyclin).

They are also bronchodilators, vasodilators, body temperature regulators (PGE specifically) and they increase GI motility.
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