MSK final exam

what are the gold compounds

mechanism is inhibition of lysosomal enzymes which releases of which promotes, not useful for nonrheumatic arthritis, gold sodium thiomalate, aurothioglucose, and auranofin

what are the types of gold compounds

gold sodium thiomalate treats active adult and juvenile rheumatoid arthritis as one part of complete therapy program, aurothioglucose adjunctive treatments of adults and juvenile rheumatoid arthritis

what are side effects of gold compounds

toxic side effects as high as 55%, serious toxicity 5-10%, dermatitis, mouth lesion, pulmonary disorders, nephritis, and hematologic disorder, less common is GI disturbances, ocular toxicity and hepatitis, to reverse chealting agensts dimercaprol and penicillamine

what are the antimalarials

chloroquine treatment of rheumatoid arthritis, beneficials effects are noted only after 1-2 months, can cause severe and sometimes irreversible AEs, on the eye skin CNS and bone marrow, , and has adverse effects for retinal damage

what are immunosuppressants for inflammatory disorders

are cytotoxic act in the steps involved in inflammatory disorders, are inficated for severe rheumatoid arthritis

what is leflunomide

immunosuppressant for RA, is a pyrimidine synthesis inhibitor and it is anti-inflammatory and immunosuppressive it is a prodrug and is teratogenic

what is azathioprine

a purine analog and an antimetabolite, N/V hepatitis, abdominal pain, reversible bone marrow depression and teratogenic

what is cyclophosphamide

immunosuppressant for refractory ra, usually life threatening, is teratogenic bone marrow depression, bladder cancer and other malignant disease

what is methotrexate

an antifolate drug approved for the treatment of severe active rheumatoid arthritis in adults who are intolerant to or have had an insufficient response to first line therapy, life threating drug interaction are known to occur between methotrexate and nsaid probenecid and penicillin G, require monitoring of liver enzymes and is CI in those with hepatic disease and in women considering pregnancy

what are antirheumatic drugs

cytokine T cell and TNF inhibitors

what are the TNF blockers

Etanercept, infliximab, adalimumab, and rituximab, are recombinant human IgG1 monoclonal antibody targeting for human TNF alpha, infliximab may worsen congestive heart failure

what are interleukin-receptor antagonist

IL-1 is cytokine for which produces inflammatory stimuli and that mediates various physiologic response anakinra is a recombinant IL-1 antagonsit, and Tocilizumab

what is gout

characterized by elevated levels of uric acid in the plasma and urine, a common form inflammatory arthritis, most commonly in men, is due to increase urate that is from biosynthesis and decreased urinary excretion of uric acid or both, gout increased risk of kidney stone is made from xanthine by xanthine oxidase

what is treatment of acute gout strategies

control of acute attacks by drugs that reduce inflammation caused by deposition of urate crystal, and increasing the rate of uric acid excretion and inhibiting the biosynthesis of uric acid by inhibiting xanthine oxidase

what is colchicine

relieves the pain of acute gout and is drug of choice, does not alter serum level of uric acid just retards the inflammation processes started by the deposition of urate crystal, AES bone marrow depression, aplastic anemia and GI disturbances

what is probenecid and sulfinpyrazone

promote the excretion of uric acid by inhibiting the URAT1 decreasing the reabsorption of uric acid leading to reduced gout attacks, does not help acute gout, do not use in people who have had uric acid kidney stones, effects are antagonized by salicylates

what is allopurinol

drug of choice to prevent gout attacks, cant terminate acute attack once begun, inhibits xanthine oxidase and block the formation of uric acid, salicylates do not interfere with action

what is febuxostat

nonpurine selective xanthine oxidase inhibitor, less sides effects compared to allopurinol

what is pegloticase

treat chronic gout for patient where small molecule therapy does not work, enhance uric acid excretion by catalyzing the oxidation of uric acid it into a smaller metabolite,

what are dendritic cells

located under skin and mucosa, captures foreign antigens, transports to lymph nodes, expressed in MHC 1 (B-cells) and MHC II (T-Cells) present antigens to adaptive immune system and helper T-cells

how do B-lymphocytes make antibodies

maturate in the bone, posses b cell receptors, develop into mature cells, bind to and are activated by dendritic cells and programmed into a single type of anitbody

what is IgG

70% of the antibodies in blood, primary antibody in the humoral response to vaccines

what is IgA

secretory Ab found in saliva, tears, colostrum, bronchial mucus, intestinal and urinary tract secretions, responsible for passive immunity passed during breast feeding

what is IgM

activates complement and enhances phagocytosis

what is IgD

primary antibody in autoimmune disease

what is IgE

primary function in immediate hypersensitivity

what is antibodies

glycoproteins, composed of 4 proteins joined by disulfide bonds, heavy chains and light chains, constant and variable, variable regions are the fragment antigen binding sites, heavy chain constant regions to form the Fc, major source of cross species immunogenicity

what is antigen, immunogen and haptens

antigens are foreign molecules that bind to the Fab of an antibody, Ag that binds to Ab but are not immunogenic are haptens, immunogen is an antibody that leads to production of antibodies haptens are immunogenic carriers

what are the determinants

portion of an Ag that binds to the Fab on an Ab there are usually many determinants on each Ag

what is titer

level of circulating specifics Abs in the blood after immunization

what is polyclonal Abs

mixture of different determinants of an Ag results from immunization of an animal

what is monoclonal Abs

composed of a single type of IgG that binds a single determinant on an antigen

how are polyclonal abs made

produced by vaccination of an animal an antigen, the humoral immune response leads to secretion of many non identical abs that bind to the Ag, polyclonal are then purified

how are monoclonal antibodies made

monoclonal are made by immunization a mouse, then the mouse spleen is harvested to isolate B-cells, B-cells are fused tumor cells to form immortal hybridoma cells that secrete abs, the hybridomas cells are screened for abs that binds to the Ag with the desired specificity and affinity then they are expanded and grow

what is a mouse mab

causes an immune response and lead to HAMAs after repeated dosing

what is a human MAb

non-immunogenic but impossible to produce in human

what is chimeric mab

constant region from human spliced with variable regions from mouse less immunogenic possessing a longer PK half life

what is humanized MAb

95% human protein structure fused with 5 % mouse structure

what is fully human mab

produced in transgenic mice that produce non-immunogenic human IgG Mab with a long PK half-life

what is complementarity determining regions

antigen binding region of the Fab, there are six present are the hypervariable regions in the FAb they are derived from mice and then converted into humanized MAbs

what is generation of human antibodies by phage display

isolate the human B-cells from peripheral blood, purify mRNA and PCR amplification of Vh and VL, clome scFv phage or express Fab in yeast or mammalian cells, capture and screen scFV and sequence amino acids sequence and clone

what is the production of transgenic mice

transform mouse embryonic stem cells with yeast artificial chromosome containing human genome, target gene deletion of mouse igG in stem cells, produces two strain of mice when crossed generate fully human antibodies by isolation of spleen cells and generation of hybridomas

what is symptoms of RA

long-lasting chronic disease of joints, warm swollen and painful joints, pain and stiffness worsen following rest, may involve inflammation of heart and lungs

what are treatments of Ra DMARs

hydroxychloroquine and methotrexate

what is the anatomy of Ra joints

inflammatory disease of the synovial joint of non weight bearing joints, invasion of B and Tc cells, genetically linked and smoking is a risk factor

what is cells and cytokines involved in Ra

dendritic cells bind to T cells causing secretion of cytokines including TNF, T cells bind to macrophages secretion of cytokines, the b and T cells surround follicular dendritic cells to form unique diffuse and aggregation patterns that secrete TNF-alpha an interact with synoviocytes, and B cells attract other pro inflammatories

what is potential mechanism of Anti-TNF

Anti-TNF neutralize surface bound and soluble TNF, Anti TNF bind TNF and facilitates cell death, and cell surface fragment crystallizable receptor and immobilized TNF alpha onto cell surface

what is potential mechanism of MAb medicated depletion of B-cells

antibody-dependent cellular toxicity - binds and has a macrophage kill the B cell, Complement dependent cytotoxicity bind complement and kill b cell, and lipid raft medicated apoptosis directly killing the B cell

what are the main B cell antigens with MAb

CD20

what is infliximab

murine chimera (remicade) is IV dosing every 6-8 weeks

what is adalimumab

fully human Humira subcutaneous every other week

what is Golimumab

fully human (simponi) subcutaneous once a month

what is Certolizumab pegol

pegylated humanized Fab (cimzia) subcutaneous every other week

what is etanercept

TNF-R Fc fusion protein (enbrel) subcutaneous once or twice a week lower incidence of infection

what are AEs of TNF-alpha

increase risk of infection and increase risk of malgnancies

what is rituximab

B-cell depletion therapies, is chimeric human/mouse MAb, IV over 2.5 hours

what is tocilizumab

B-cell depletion therapy is humanized MAb directed against IL-6 receptor on the surface of B-cells by ADCC, CDC and apoptosis, IV and SC sarilumab

what is T cell modulation

Abatacept ir Orencia is IgG linked to CTLA-4 which inhibits CD80 on APCs slows T-cell activation and production of cytokines decreasing the inflammatory response

what is osteoarthritis

joint specific disease related to breakdown of cartilage and bone usually in the hip and knee, decrease in proteoglycan results in degradation of cartilage lose of meniscus and bone on bone chronic pain no biologics

what is SLE

chronic autoimmune disease generation of anti-nuclear autoantibodies leads to inflammation, multiple symptoms can relate to inflammation and heart disease treatment is hydroxychloroquine and methotrexate Belimumab and anifrolumab is a monoclonal antibody that can be used

what is belimumab

monoclonal antibody used to treat SLE, binds to B-cell activating factor receptor and inhibits the proliferation of B-cells,

what is anifrolumab

newest FDA approved MAb treating SLE, binds to IFAR ½ blocking INF alpha and beta, dose is 300mg IV over 30 minutes every 4 weeks, AEs infection

what is osteoporosis

weakening of bone resulting in an increased risk of breaks common with aging, underlying causes in imbalance of osteoclast and osteoblast treatment is prolia and Romosozumab

what is prolia

binds RANKL blocking maturation of pre-osteoclasts into osteoclates protecting the degradation

what is romosozumab

inhibits sclerostin a regulatory factor in bone metabolism increase bone formation to lesser extent decreases bone resportion

what is gout

inflammatory arthritis disease characterized by flare ups that most often occurs in the largest metatarsophalangeal joint, mechanism involved crystallization of excess uric acid resulting in inflammatory cascade

what is RA

chronic systemic autoimmune inflammatory disease in small joints age is 50-75 underlying causes in unknown causes inflammation of the synovial joint

what is extra-articular involvement for RA

rheumatoid nodules, vasculitis, pulmonary complications, ocular manifestation, cardiac involvement or felty’s syndrome

what is comorbid conditions of Ra

cardiovascular disease, infections, malignancy, and osteoporosis

what is presentation of Ra

no single clinical radiologic or serologic test, key features are prodromal symptoms such as fatigue weakness low grade fever loss of appetite, joint pain stiffness and muscle ache, evidence of clinical joint swelling, morning stiffness, generalized complaints and examination of hands/wrist

what are labs test of Ra

rheumatoid factor is not specific but if synovitis is high probability, may be seronegative early in the disease, CCP helpful for diagnosis but not useful for assessing disease activity and acute phase reactants both test are useful but not very specific

what are radiographic findings in Ra

not required for diagnosis but recommended to obtain imaging at time of diagnosis to assess for joint space narrowing

what is the course of clinical remission

long clinical remission in 10%, intermittent disease is 15-30% relapses often highlighted by involvement of more joints and progressive disease is majority of patients

what are short term treatments for Ra flares

NSAID and corticosteroids (prednisone 15mg/day) ideally for under 3 months for bridging, modification of DMARD and managing flares

what is hydroxychloroquine for Ra

first line if moderate Ra, onset is 3-6 months, watch for loss of vision, is the saftest DMARD not the most effective that why it is for moderate

what is methotrexate for Ra

dose is once weekly maybe twice weekly, need to take folic acid 1 mg dialy with it takes 4-6 weeks onset GI nauea vomiting diarrhea stomatitis thrombocytopenia and leukopenia, CI in CKD 4/5 liver disease, and heavy alcohol use, avoid in pregnancy and drug interaction with NSAID

what is leflunomide

similar to methotrexate no as flexible dosing onset within a month AEs diarrhea alopecia rah and increase level alternative to methotrexate no stomatitis do not use in pregnancy

what is sulfasalazine

use to treat Ra onset 1-2 months Aes nausea anorexia diarrhea rash, rate is lupus like syndrome elevation in hepatic enzymes leukopenia can use in pregnancy

what is biologic DMARDs

used after failure of csDMARDs these agents will target TNF IL-6 all have similar efficacy work best when combined with methotrexate need to screen for TB underlying infection and live vaccinations

what are TNF inhibitors

select based on SQ or IV if one rejects class still can work if secondary if no primary response class may not work caution in those with heart failure and serious infections

what is IL-6 receptor inhibitors

preferred when patient do not tolerate TNFs require monitoring neutropenia thrombocytopenia hepatotoxicity, and hyperlipidemia and increased risk of GI perforation

what is Tocilizumab and arilumab

IL-6 SQ every other week, approved for treatment

what is rituximab

for Ra two 100mg IV infusion separated by 2 weeks after 6 months targetrs CD20 positive B-cells onset within 16 weeks

what are JAK inhibitors

can be used to treat Ra major cardiac events, venous thrombosis, herpes zoster, malignancy need to screen for TB and herpes zoster tofacitinib , barictinib and upatacitinib

what are pre-treatment steps for Ra

early recognition ideally within 3 months, prevent irreversible joint destruction, patient education exercise, dietary counseling, pretreatment assessment is routine labs, screen for hepatis, assess CV risk, terat to target approach reevaluate in 3 months

what is initiating therapy for Ra

disease duration should be considered if low start hydroxychloroquine sulfasalazine then methotrexate, if moderate ot hihg start methotrexate

when should DMARDs be switched

50% improvement in symptoms after 3 month or remission if still moderate can add a TNF biologic

what should be used in pregnancy for Ra

hydroxychloroquine TNF inhibitors and sulfasalzine

what is SLE

chronic autoimmune disease, progressive unknown cause effects multiple organs comorbidities are depends on location for autoantibodies against body can have drug induced lupus as well

what is drug induced lupus

10% of lupus can be caused by procainamide and hydrolase mainly also can be caused by carbamazepine isoniazid methyldopa minocycline sulfasalazine and quinidine

what is musculoskeletal lupus

arthralgias and myalgias very common all major and minor joints can be affected presents as stiff joint and usually short duration if sever add steroid and base treat with hydroxychloroquine

what is constitutional lupus

fatigue fever weight loss considered non-specific symptoms are seen frequently

what is mucocutaneous lupus

butterfly rash photosensitivity, raynaud phenomenon discoid lupus almost as common as musculoskeletal complains, butterfly rash most common discoid lupus labeled as chronic skin condition with sore/infl use hydroxychloroquine and some times topical steroids if escalate use methotrexate or mycophenolate

what is renal lupus

lupus nephritis may be mild to moderate need to monitor renal function those presenting with nephritis have the worse outcomes management if not bad can use corticosteroid and immunosuppressant if bad IV corticosteroids and methylprednisolone and add mycophenolate or cyclophosphamide

what is lab data for lupus

typical lab values, highly specific test are anti-smith and anti-double stranded DNA test ANA test is diagnostic the higher the more specific 1:80 id diagnostic of lupus

what are medication for managing lupus

hydroxychloroquine is first line dose is 5mg/kg/day max 400 once or twice daily dosing, NSAIDs and corticosteroids (steroids are main treatment)are used for flares dosing is 5-15 mild to moderate moderate to severe is 1mg/kg/day and major is IV with methylprednisolone to follow methotrexate, cyclophosphamide, mycophenolate, voclosporin and azathioprine are alternatives

what is azathioprine

alternative for lupus, inactive until metabolism mycophenolate is favored as alternative over but can use in pregnancy

what is cyclophosphamide

alkylating agents depletes T and B cells and suppress antibody producing dosing is based of BSA and white people get lower doses, very toxic myelosuppression, malignancy immunosuppression and hemorrhagic cystitis

what is mycophenolate

prodrug good alternative for lupus, dosing is 500-3000mg daily Aes mainly Gi but it does have REMS for pregnancy must stop 6 weeks before getting pregnant

what is voclosporin

used to treat moderate to severe lupus is a calcineurin inhibitor do not use below 45 eGFR monitor BP increase risked of infection avoid in pregnancy and people taklong strong CYP inhibitors