immunopharmacology Flashcards
calcineurin inhibitors
cyclosporin A
Tacrolimus (FK506),
(Pimecrolimus)
mTOR inhibitor
Sirolimus (rapamycin)
(everolimus
temsirolimus)
JAK kinase inhibitors
Tofacinitib
(Baricitinib
Ruxolitinib
Upadacitinib)
inhibitors of purin or pyrimidine synthesis
methotraxate
leflunomide
Azathioprine
Myclophenolate Mofetil
alkylating agents
cyclophoyphamide
BLOCKING T CELL SURFACE MOLECULES INVOLVED IN SIGNALING OF IMMUNOGLOBULINS
ANTITHYMOCYTE GLOBULIN (ATG)
Rho (D) immunoglobulin; Antilymphocyte globulins (ALG)
ANTIBODIES AGAINST T CELLS
not on the list
Basiliximab
Muromonab-CD3
ANTIBODIES AGAINST B CELLS
RITUXIMAB
ANTIBODIES AGAINST TNFa
INFLIXIMAB; ADALIMUMAB
ANTIBODIES AGAINST IL-1ß
NOT ON THE LIST
Canakinumab, Rilonacept
ANTIBODIES AGAINST Il-6R
TOCILIZUMAB
Sarilumab
ANTIBODIES AGAINST IL-17
not on the list
Secukinumab, Ixekizumab
ANTIBODIES AGAINST IL-12/23
USTEKINUMAB
ANTIBODIES AGAINST alpha4-integrin
NATALIZUMAB
ANTIBODIES AGAINST IL-13R and IL-4alpha-R
DUPILUMAB
CTLA 4/Fc fusionprotein
ABATACEPT (betalacept)
calcineurin function
Tcell receptor activation results in Ca+2 influx, activation of calcineurin by Ca+2 (phosphatase), dephosphorylation of NFAT results in its movement to the nucleus, in concert with other nuclear factors -> activation of genes encoding cytokines ( IL-2) r-> release -> cell mediated immune response
cyclosporin A
calcineurin inhibitor, blocks IL1+2
inhibits secondarily macrophage-T-cell-interaction, T-cell responsiveness, T-cell-dependen-B-cell function
forms a complex with cyclophylline
blocks cellular immunity ,
IV solvent can cause anaphylaxis, oral bioavailabilty is 20-50 % , grapefruit juice increases bioavailability by as much as 63%, CYP3A4
SE: nephrotoxicity, hepatotoxicity, hypertension, hyperglycemia, gingival hyperplasia, hirsutism, CNS disorders,stirelity, cardiotoxicity, neurotoxicity, neutropenia, (anemia), thrombocytopenia,
Bladder cancer is rare but must be looked for every 5 years
Indication: RA, (SLE, polymyositis, dermatomyositis, JCA, Behcet disease, Wegener granulomatosis)
isolated from polypocladium inflatum
Tacrolimus
Pimercrolimus
(isolated from Streptomyces tsubaensis).
It binds to FKBP 12 (FK Binding Protein,
macrophyllin) (peptidylprolyl) . The complex blocks calcineurin
more potent than cyclosporin A
Pimercrolimus is a local drug
Use: transplants, Auto-Immune-diseases, GVH, creme for atopic dermatitis + psoriasis
SE: no gingival hyperplasia, more psychological problems,
nephrotoxicity, hepatotoxicity, hypertension, hyperglycemia, neurotoxicity , hyperkalemia´GTI problems
hirsutism
T-cell immunosuppression
(image)
SIROLIMUS
(rapamycin)
(Everolimus,Temsirolimus)
similiar to Tacrolimus, binds FKBP 12, but the complex binds mTOR, mTOR has a central role in the IL2 activation pathway in lymphocytes, inhibit T-cell proliferation and maybe also B-cell proliferation and immunoglobulin production
Everolimus
and Temsirolimus are semisynthetic variants
They block T AND B cell function
sirolimus and everolimus are orally administered, temsirolimus iv.
Oral
availability of sirolimus is very variable and has a very long half-life (60h).
metabolized by CYP3A4
Use: kidney transplant and GVH. coronary stents(drug eluting stents),
Everolimus is used for breast cancer, kidney cc., neuroendocrine tumors, astrocytoma and sclerosis tuberosa,
temsirolismus for mantle-cell lymphoma and kidney cc.
SE: BM supression (thrombocytopenia!), hepatotoxicity, pneumonitis, hyperglycemia, hyperlipidemia, GI disturbance, headache
JAK signaling
two waves mediated by STAT5, JAK1+3 work in concert after IL-2-R is activated. if we block JAK 1+3 both waves are inhibited, if we block JAK 3 ( and PI3K+ mTOR partially) just the second wave is inhibited
TOFACITINIB
BARICITINIB, UPADACITINIB
(RUXOLITINIB)
Tofacitinib mostly inhibits JAK 1 and 3 – it blocks IL2 (4, 6, 7, 9, 15 and 21) mediated
pathways in T cells . reduces NK-cells, serum immunoglobulins and CRP
JAK1/JAK3 complex mediates signal from IL2-R-> Tofacitinib blocks IL (…) production ans secondary B-cell activation etc. …
JAK1 controls signal transduction of IL6 and interferon receptor
Baricitinib blocks JAK 1 and 2.
(Ruxolitinib JAK 2)
upadacitinib- JAK-1
They are low molecular weight drugs
Kinetics: Orally administered, good bioavailability 74%.
Tofacitinib has a short half-life
(prolonged release forms are available),
baricitinib and upadacitinib have longer halflife. Tofacitinib is mostly metabolized by CYP3A4 and lesser extend CYP2C19, baricitinib is mostly eliminated by kidney.
Use: they are used for RA. They can be used alone or in combination with MTX. The monotherapy is similarly effective as a MTX + antiTNFα combination. Other indications are under investigation (UC, CD, psoriasis, PsA, JIA, spondyloarthritis?).
(Ruxolitinib: polycytemia vera, myelofibrosis)
Also Organ allograft rejection,
Adverse effects: infections (airway)+ UTI, hyperlipidemia, CK elevation, liver enzyme elevation, BM suppression. , virus reactivation (HZV), TBC, LDL-level,
malignancies (e.g. lymphomas, lung, breast etc.), thromboembolism, hepatotoxicity,
anemia, thrombocytosis (baricitinib), neutropenia, GI perforations,
intersticial lung disease (tofacitinib)
(MTX combination is more dangerous)
black box warning for malgnancies and infections
Inhibitors of cytokine gene expression
Corticosteroids Prednisone Prednisolone Methylprednisolone Dexamethasone
They have both anti-inflammatory
action and immunosuppressant
effects
Mechanism of action
Binds to glucocorticoid receptors and the complex interacts with DNA to inhibit
gene transcription of inflammatory genes.
Decreased production of inflammatory mediators as prostaglandins,
leukotrienes, histamine, PAF, bradykinin.
Decreased production of cytokines IL-1, IL-2, interferon, TNF.
Stabilizes lysosomal membranes.
-Decrease generation of IgG, nitric oxide and histamine.
Inhibit antigen processing by macrophages.
Suppress T-cell helper function.
Decrease T lymphocyte proliferation
First line therapy for solid organ allografts & haematopoietic stem cell
transplantation.
Autoimmune diseases as refractory rheumatoid arthritis, systemic lupus
erythematosus (SLE), asthma.
Acute or chronic rejection of solid organ allografts.
Often used locally in dermatology
Adverse Effects Adrenal suppression Osteoporosis Hypercholesterolemia Hyperglycemia Hypertension Cataract Infection etc....
Methotrexate
Mech. of action: antimetabolite, Inhibition of DHF-reductase and depletion of folic acid leads to the blockade of DNA synthesis. The anti-inflammatory mechanism is likely the inhibition of AICAR transformilase by MTX-polyglutamates
◦ Inhibits several enzymes, including:
◦ dihydrofolate-reductase
◦ 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) formyltransferase (ATIC)
-AICAR inhibits competitively AMP deaminase - AMP accumulation, AMP is converted extracellular to adenosine which is a potent inhibitor of inflammation
- thymidylate synthase
accumulation of AICAR intracellularly and adenosine extracellularly
inhibition of both B and T-cell activation (interestingly TNF) macrophages and dendritic cells
secondary effects on PMC chemotaxis
-stimulates apoptosis in inflamatory cells
-inhibits proinflammatory cytokines linked to rheumatoid synovitis
upregulates adenosine receptors)
The polyglutamates of MTX persist in cells longer
In autoimmune diseases (RA, psoriasis – and other dermatological diseases, SLE, IBDs, JCA, PA, AS, POLYMYOSITIS, Dermatomyositis, Wegeners granulomatosis, giant cell arteritis, vasculitis)
If it is needed it can be given sc. as well.
oral bioavailability is 70%
hydroxychloroguin can reduce the excretion and increase the tubular reabsorption
30%bile excretion but primarily in kidney
Adverse effects:
#alopecia
#leukopenia, anemia
Liver enzyme elevation, hepatotoxocity
Fibrotic pneumonitis (hypersensitivity reaction)
Infection
GI problems (mucositis, stomatitis, diarrhea, ulcer, nausea)
(BM suppression)
Liver toxicity can be alleviated by leucovorin administration (next day after) or folic acid - reduce efficacy 10%
teratogenic
LEFLUNOMIDE
Teriflunomide
Mech. of action: They are inhibitors of dihydroorotate-dehydrogenase – this blocks
the pyrimidin synthesis. Arrest in G1 -phase. Teriflunomid is the activ metabolite of leflunomide.
They block T-cell proliferation and AB production of B-cells
secondarily increase in IL-10receptor mRNA; decrease in IL-8 receptor mRNA, an decrreased NF-kB activation (TNFa dependent)
Leflunomide is registered for RA and similarly as effective as MTX. Teriflunomide is
the active metabolite of leflunomide, it is used for remitting-relapsing MS
They are orally given
T1/2 is 2 weeks , enterohepaticcirculation also of active metabolite
Cholestyramine can accelerate the excretion
Adverse effects: liver enzyme elevation (up to sever liver dysfunction) diarrhea, skin exanthemas, alopecia, mild hypertension, weight gain increased BP, leukopenia and thrombocytopenia occur rarely
Azathioprine
It is transformed in the body to 6-mercaptopurine (6-MP) (book: 6-thioguanine). 6-MP turns to thio-IMP: it
blocks AMP and GMP synthesis.
◦ Inhibit phosphoribosyl-pyrophosphate-amido-transferase
(purine synthesis)
◦ Inhibit purine-base salvage
◦ Incorporates into nucleic acids
It is not known why azathioprin is a more specific immunosuppressive agent than 6-MP (better uptake or transformation in lymphocytes?)
blocks IL-2 secretion
Kinetic: Azathiopron is given orally or parenterally, Thio-IMP is catabolized by xanthin-oxydase.
(Cave allopurinol!)
rapid metabolizeres metabolise the drug 4x faster (bimodal metabolism in humans)
It mainly blocks cellular immunity
Use: kidney transplantations, IBDs, SLE, vasculitis diseases, (RA), PA, polymyositis, behcet disease, vasculitius
Adverse effects: BM suppression, liver toxicity (rarely: liver vein occlusion syndrome) GI disturbances, infection risk, lymphomas, allergic reaction
mycophenolate mofetil
It is isolated from Penicillium sp.
Mycophenolate is converted to mycophenolic acid (active form), blocks inosine-monophosphate-dehydrogenase (de novo GMP
synthesis). Lymphocyte (b-cell +T-cell) cannot use salvage-way for nucleotide uptake (they are
extremely sensitive to de-novo blockade), blocks proliferation
interferes with leukocyte adhesion downstream by inhibiting E-selectin and P-selectin, and intracellular adhesion molecule 1
Use: organ transplantations (1st of choice for heart, liver and kidney). Off label: GVH, SLE, RA, nephritis, myasthenia, psoriasis, wegeners granulomatosisa ) prevent chronic allograft vasculopathy in cardiac recioient patients (1st line), acute and chronic GVH,
generally an alternative to cyclosporin and tacrolimus for patients who do not tolerate those
Adverse effects: BM suppression, GI disorders, hypertension, nausea, dyspepsia, hepatotoxicity , infection and rarely malignancy, prevent chronic
CYCLOPHOSPHAMIDE
Derived from mustard gas, the group called bis(chlorethyl)amine
Prodrug: it turns in more steps in the body into phosphoramide mustard (the
active form) and into acrolein (inactive but toxic)
Phosphoramide mustard is a bifunctional alkytating agent. It alkylates DNA mostly on N7 of guanosine. It forms cross-links inside of DNA chain or between the two chains to prevent cell replication
It inhibits both T and B cells by 30-40%
Used: in SLE, systemic sclerosis,
vasculitis diseases, wegeners granulomatosis autoimmune glomerulonephritis, AI hemolytic anemia,
Transplant stem cell procedures, but does not prevent GVH disease,
Adverse effects: BM suppression (pancytopenia), oligospermia, ovarian dysfunction, GI, cardiac toxicity, hemorrhagic cystitis (akrolein), teratogenity and possible mutagenity, may cause hemorrhagic cystitis (treated with mesna), electrolyte disturbances
HIGH DOSE IMMUNGLOBULIN MIX
IVIG
It is isolated from the blood of healthy donors and iv. given.
The IG mix can be used for the treatment of IG deficit. It can also be used as an immune modulator: to neutralize superantigens and autoantibodies, to block Fc receptors of macrophages, to inhibit the complement and immuncomplex mediated tissue destruction.
Use: ITP, Kawasaki-Sy., Guillain-Barre Sy., Polymyositis, Vasculitis, SLE and IG deficit
Adverse effects: allergic reactions
Anti Rh0
(D): concentrated solution from human source. It must be given after delivery of
Rh+ baby of Rh- mother to suppress own antibody generation
POLYCLONAL ANTIBODIES
ANTI-LYMPHOCYTE AND ANTI-TYMOCYTE
GLOBULINS (ALG AND ATG)
They are isolated from blood of rabbits or horses immunized by human lymphocytes or thymocytes. It kills and blocks lymphocytes in the body.
Use: it is the most effective agents against acute rejection of grafts after transplantation. It is used if the possibility of rejection is high. In BM transplantation
the pretreatment of the graft by ALG reduces the possibility of GVH.
Adverse effects: dyspnoe, serumdisease, fever, GI disturbances
(Hyperimmunglobulins (human or animal) are used against viral infections (passive immunization for CMV, VZV, HBV, Rabies) or for toxicology (dioxin, snake venoms etc.). For RSV (palivizumab) and against B toxin of C. difficile (bezlotoxumab) monoclonal AB are available. )
-momab
100% murine
Mouse
-ximab
75% human
25% murine
Chimera
-zumab
95% human
5 % murin
Humanized
-umab
100% human
Human
MUROMONAB
not on the list
Monoclonal recombinant murine AB against CD3 coreceptor of TCR.
it is older than the nomenclature. (-momab)
It reduces T-cell count rapidly.
Use: It is given for kidney
transplantation against acute rejection
Adverse effect: cytokine release
syndrome (Flu like symptoms,
sometimes shock)
BASILIXIMAB (DACLIZUMAB)
not on the list
Antibody against IL-2 receptor. against T-cell. It inhibits the activation of lymphocytes but it does not kill them.
Use: it can be used in solid
organ transplantations against
acute rejection, but it is less
effective than ALG or ATG
Adverse effects: GI symptoms
RITUXIMAB
OCRELIZUMAB
They bind to CD20 antigen both of normal and malignant B-cells. They dramatically reduce (after one treatment) B-cell count for many (6-9) months (true for non malignant cases) through complement and cell (macrophage, neutrophil or NK) mediated pathway.
They can cause apoptosis as well.
Use: originally rituximab was developed for low malignant B-cellular lymphomas and CLL. In RA it is given periodically (2 doses in 2 weeks and after 6 month break). It is also registered for vasculitis diseases. Off label it can be used for more therapy resistant autoimmune diseases and organtranstplantation. Ocrelizumab is registered for MS (also for progressive type).
Adverse effects: infusion-reactions (steroid, paracetamol and antihistamine prophylaxis needed), infections (serious viral, bacterial or fungal), malignancies, infusion reaction, arrhythmias (rare), angina (rare), late onset neutropenia, rash, HBV screening, reactivation of tuberculosis, lymphoma, fatal mucocutaneous reaction, cytopenias
◦ Broad off-label use
Other CD20 antibodies for treatment of tumors: Obinutuzumab, Ofatumumab, Y90-
Ibritumomab-tiuxetan, Veltuzumab
Alemtuzumab
not on the list
Antibody against CD52 that is abundant on B-, T-, NK cells and macrophages. Originally it was developed for B-cellular CLL (withdrawn). Today it is indicated for MS. It depletes autoimmune B and T cells. The repopulation normalizes immune balance.
Adverse effect: BM suppression
Etanercept
not on the list
Fusionprotein of 2 TNFαR and Fc
Use: sc. 1-2 x / week
ANTI-TNFa TREATMENT
Ethanercept is not effective in IBDs – it could worsen the symptoms possible because it cannot neutralize bound TNFα. In RA, JIA, Bechterew, psoriasis all TNFα
blockers have similar effectivity. They could be used for uveitis as well.
In RA they are mostly combined with MTX, but monotherapy is also possible
Side effects: risk of infections (tuberculosis, opportunistic infections, activation of
latent viral hepatitis), infections site and infusion reactions, allergy
INFLIXIMAB
Chimera AB
IgG1 binds soluble and possible membrane-bound TNFa. (same as adalimumab)
Use: iv. once / 2 month
half life is 9-12 days
Biosimilars are available
ANTI-TNFa TREATMENT
registered for RA, JIA, Bechterew’s disease
(ankylosing spondylitis), psoriasis and both IBDs, PsA
off label : vasculitis (different types), uveitis, sarcoidosis,
In RA they are mostly combined with MTX, but monotherapy is also possible (or antimalaria drugs, azathioprine, leflunomide, cyclosporin)
Neutralizing AB formation is possible (more often against infliximab)
Side effects: risk of infections (tuberculosis, opportunistic infections, activation of
latent viral hepatitis), infections site and infusion reactions, allergy
MTX reduces the occurence of human antichimeric antibodies
ADALIMUMAB
Human AB IgG1, binds with soluble TNFa and prevents interaction with p55 and p75 cell surface receptor
this results in downregulation of macrophage and T-cell function
Use sc. once/2 wekks
ANTI-TNFa TREATMENT
Half life is 10-20 days
clearance is decreased by 40% in the presence of MTX (+reduction of antihuman AB)
registered for RA, JIA, Bechterew’s disease
(ankylosing spondylitis), psoriasis and both IBDs,PsA, plaque psoriasis, Behcet disease, sarcoidosis, noninfectious uveitis.
In RA they are mostly combined with MTX, but monotherapy is also possible.
Side effects: risk of infections (tuberculosis, opportunistic infections, activation of
latent viral hepatitis), infections site and infusion reactions, allergy
Golimumab
not on the list
Human AB
Use sc. once / month
ANTI-TNFa TREATMENT
s. Golimumab has not yet registered
for CD
Side effects: risk of infections (tuberculosis, opportunistic infections, activation of
latent viral hepatitis), infections site and infusion reactions, allergy
Certolizumab Pegol
not on the list
-Humanized AB Fab fragment bound to Polyethylenglycol (Pegylated) -Use sc. once / 2 week or 1 month ANTI-TNFa TREATMENT
Certolizumab is only indicated for RA – it can have small difference in
effect, because it does not activate complement system
In RA they are mostly combined with MTX, but monotherapy is also possible
Side effects: risk of infections (tuberculosis, opportunistic infections, activation of
latent viral hepatitis), infections site and infusion reactions, allergy
TOCILIZUMAB
Sarilumab
IL-6-R antobody (soluble or membrane bound)
They block the receptor (not the cytokine itself)
Inhibit B-cell activation, differentiation of naive CD4+ T cell
Th17
-systhesis of acute phase proteins
◦ Very efficient in monotherapy, without csDMARDs
Use: Tocilizumab is for RA and JIA, SysSclerosis,
sarilumab is still for RA only., SJIA, PJIA,
Tocilizumab is given monthly iv., sarilumab iv. or sc. in 2 weeks
half life is 11 days
combination or monotherapy
Adverse effects: similar to TNFα inh., neutropenia, lipid level increase (LDL), thrombocytopenia, , infections (tuberculosis, fungal, viral), URespiratoryTI, headache, hypertension, anaphylaxis (fewer than 1%),
Belimumab
not on the list
Antibody against B-Lymphocyte-Stimulator-Protein (BLyS, BAFF). It
inhibits the survival of autoreactive B-cells and the differentiation into
plasmocytes. It normalizes low complement level in SLE.
Use: it is registered till now for SLE
SE: fever, leucocytopenia, migraine, arthralgy
USTEKINUMAB
fully human IgG It binds to the common p40 subunit of IL-12 and IL-23. IL-12 would activate the formation of Th1 (CD4+) and NK-cells, while IL-23 activates Th17 proinflammatory lymphocytes. bioavailability 57 % sc. elimination half life: 10-126 days monotherapy or combination with MTX
Use: it is used for psoriasis (Plaque Psoriasis and Arthritis Psoriatica) PsA and for CD.
Adverse effects: Infections (UrespTI), maybe malignancy, reversible posterior leukoencephalopathy syndrome
Guselkumab,
Tildrakizumab, Rizankizumab
(NOT ON THE LIST)
anti IL-23 antibody
IL-23 activated Th17-cells
till now for Plaque Psoriasis registered
Secukinumb, Ixekizumab
not on the list
THEY BLOCK THE PROINFLAMMATORY CYTOKINE IL-17
PRODUCED BY TH17 CELLS
USE: PSORIASIS (PLAQUE PSORIASIS AND ARTHRITIS
PSORIATICA - SECUKINUMAB) , BECHTEREW’S DISEASE
(SECUKINUMAB), THEY ARE INEFFECTIVE IN CD!
ADVERSE EFFECTS: INFECTIONS (RESPIRATORY), ALLERGY
(RHINITIS)
Brodalumab
NOT ON THE LIST
ANTI IL-17R ANTIBODY
Registered for plaque psoriasis
Adverse effects : arthalgia, headache, tiredness, diarrhea, stomachache
Anakinra
not on the list
It is a long acting analogue of the endogenous IL-1R antagonist peptide
inhibits the activation of neutrophils
Use: In RA it seems less effective than TNFα blockers. Otherwise it is indicated
for cryopyrin-associated periodic Syndromes (CAPS)
It has similar side effects as TNFα blockers (milder). It mustn’t be combine with
them.
Daily sc. Administered
Canakinumab, Rilonacept
not on the list
Anti IL-1β bilogicals
Patients with CAPS have mutation on NLRP-3 gene. This mutation causes an
excessive release of IL-1β in certain situations. It causes fever, exanthemas and
arthralgia etc.
Use: cryopyrin-associated periodic syndrome (CAPS), JIA, gout
Adverse effects: headache, dizziness, weight gain, infections
Anti IL-5 AB
not on the list
Reslizumab
IT IS USED FOR SEVERE EOSINOPHILIC BRONCHIAL ASTHMA
ADVERSE EFF: CK ELEVATION, ALLERGIC REACTION
ANti IL-5R AB
not on the list
Benralizumab
IT IS USED FOR SEVERE EOSINOPHILIC BRONCHIAL ASTHMA
ADVERSE EFF: CK ELEVATION, ALLERGIC REACTION
Reslizumab
not on the list
ANti IL-5 AB
IT IS USED FOR SEVERE EOSINOPHILIC BRONCHIAL ASTHMA
ADVERSE EFF: CK ELEVATION, ALLERGIC REACTION
Benralizumab
not on the list
Anti IL-5-Receptor AB
IT IS USED FOR SEVERE EOSINOPHILIC BRONCHIAL ASTHMA
ADVERSE EFF: CK ELEVATION, ALLERGIC REACTION
DUPILUMAB
Anti IL-4αR and IL-13R AB
It blocks also Th2 medaited immunoreaction. It was registered for eosinophylic asthma and for sever atopic dermatitis
AE: Local reactions, oral herpes, coniunctivitis, AB formation
AB against CD3 coreceptor of TCR
not on the list
Muromonab
AB against IL-2 Receptor
not on the list
Basiliximab (Daclizumab)
AB against CD20
Rituximab,
Ocrelizumab
AB against CD52
not on the list
Alemtuzumab
Ab against B-lymphocyte-stimulator-protein (BlyS, BAFF)
not on the list
Belimumab
AB against IL-23
not on the list
Guselkumab, Tildrakizumab, Rizankizumab
AB against IL-17R
not on the list
Brodalumab
IL-1 Receptor antaginst
not on the list
Anakinra
Anti IL-1ß biologics
not on the list
Rilonacept
Anti IL-4αR and IL-13R AB
DUPILUMAB
ABATACEPT
CTLA-4/Fc fusionprotein
It blocks the binding of the costimulator CD28 protein to CD80/86.
(It binds to CD80/86). CD80/86 – CTLA4 interaction is inhibitory on lymphocytes. preventing the activation of T-cells
IV or sc.
serum half life: 13-16 days
Co-adminst. of corticoids. MTX or NSAIDs does not influence clearance
equivalence to adalimumab
can be used in combination with MTX or monotherapy
Use: RA, JIA (with uveitis), psoriatic arthritis, PJIA, (IBD; Sjörgensen Syndrom, SLE, DM1, psoriasis vulgaris)
Adverse effects: headache, infections, (neutralizing) AB production, concomitant use of biologics is not recommended (serious infection), tuberculosis and HBV screening, infusion related hypersensitivity reaction (including anaphylaxis; rare), possible increase in lymphoma
Anti-PD-1 Antibody
not on the list
nivolumab
Anti-CTLA-4 antibody
not on the list
ipilimumab
nivolumab
not on the list
Anti-PD-1 Antibody
ipilimumab
not on the list
Anti-CTLA-4 antibody
anti alpha-4 (of a4ß1 and a4ß7) integrin antibody
NATALIZUMAB
integrins expressed on leukocytes except neutrophils
inhibits the alpha4 mediated adhesion of leukocytes to their cognate receptor
MS and Crohn´s disease
should not be used with any of the anti-TNFa-drugs
increses risk of progressive multifocal leukoencephalopathy (JC virus?)
(Vedolizumab)
NATALIZUMAB
It inhibits the docking and extravasation of T-cells trough α4β1 – VCAM-1 interaction in CNS and α4β7
Binds to the alpha4 subunit of both the alpha4ß1 (VCAM-1 binding is inhibited) and alpha4ß7 (MadCAM-1 binding is inhibited) integrins
integrins expressed on leukocytes except neutrophils
inhibits the alpha4 mediated adhesion of leukocytes to their cognate receptor
MS and Crohn´s disease
should not be used with any of the anti-TNFa-drugs
increses risk of progressive multifocal leukoencephalopathy (JC virus?)
–
MadCAM-1 in GI Tract.
Use: It is used in MS (it not anymore used in CD)
Adverse effects: fever, nausea, infections. It can activate with ca. 1:1000 possibility polyomavirus JC (John
Cunningham). This can lead to progressive multifocal leukoencephalopathia (PML).
leukocyte adhesion is blocked
Vedolizumab
not on the list
It is selective to GI type α4β7 Integrin.
◦ Binds to the ß7 subunit of alpha4ß7 integrin (MadCAM-1 binding is
inhibited)
◦ SE: infections (nasopharyngitis, bronchitis, influenza, sinusitis),
headache, nausea, fever, fatigue, cough, joint pain
Therefore it is useful only for CD, but it
do not activates JC virus. like Natalizumab
Antibody against Fcε part of IgE
Omalizumab
Omalizumab
Antibody against Fcε part of IgE.
It can reduce circulating IgE level
up to 90%
Use: severe bronchial asthma, chronic urticaria (see in asthma chapter)
Adverse effects: allergy, local
reactions
Antibody against complement factor C5
not on the list
eculizumab
Eculizumab
not on the list
Antibody against complement factor C5 It is used for patients with paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome Orphan drug
5-aminosalicyclic-acid derivatives (5-ASA)
SULFASALAZINE ->(mesalazine) and sulphapyridin
olsalazine, balsalazide
SULFASALAZINE
Sulphasalazin is cleaved in colon to 5-ASA (mesalazine) and to sulphapyridin)
(Olsalazine and balsalazide are other prodrugs of 5-ASA.)
Sulphapyridine is resorbed from GI tract and possibly it is active in RA. 5-ASA is not absorbed and it is
important in IDB treatment.
1. 5-ASA induced PPARγ expression
a) it inhibits the activation of NFκB and
b) TLRs.
2. also blocks the function of cytokines IL-1, (IL-2,) IL-6, (IL-8, ), IL-12, TNFa
3. blocks COX and LOX
4. an antioxydant as well
Mechanism of action of sulphapyridin is
unknown
Kinetics: 10-20% of suphasalazine is absorbed (without cleaving) and partially through urine and bile excreted. Sulphapyridin is metabolized in the liver. 5-ASA remains unabsorbed
half life is: 6-17 hours
Use: Suphasalazine is used in RA, ankylosing spondylitis (Bechterew’s disease), Juvenile chronic arthritis and in IBDs. Its effectivity in RA is relatively mild. The other 5-ASA derivatives are used
for IBDs. In UC they are very effective, in CD their effectivity is questionable
Adverse effects: sulphasalazine: nausea, vomiting, headache, rash (often), BM suppression, oligospermia. Other derivates: headache, nausea (rare), diarrhea, methemoglobinemia (rare), neurtopenia>thrombocytopenia, hemolytic anemia, dsDNA, pulmonary toxicity, drug induced lupus is rare, reversible infertility in men, does not affect fertility in women,
microgranules, suppositories, enema -> Action is exerted loacally therefore early absorption must be avoided –
either prodrugs or special formulations are used
chloroquine, hydroxychloroquine
Possible mech. of action: they increase the pH in lysosomes of macrophages, and
hereby inhibit the catabolism and presentation of antigens.
Moreover they block autophagy and formation of proinflammatory mediators.
Kinetics: They are well resorbed and they have extremely large volume of distribution because tissue binding.
Half-life is long (up to 40 days). They are metabolized in liver.
Use: In RA they can be used in monotherapy only in very mild cases otherwise they can be combined with other DMARDs. In SLE and DLE they are more effective and first of choice drugs for less complicated cases. They can be used in Sjörgen’s syndrome as well.
Adverse effects: skin exanthemas, stomachache, nausea, vomiting, myopathy, nightmares, macula degeneration and cornea discoloration (ophthalmologic control is needed)
Dimethyl-fumarate
not on the list
The mechanism of action is unknown. It activates nuclear factor (erythroid-derived
2)-like 2 (Nrf2) pathway. It reduces oxidative stress.
Use: orally administered for MS. Other fumaric acid esters are used for psoriasis.
Adverse effects: lymphocytopenia, flush
Fingolimod, siponimod (ozanimod)+
not on the list
Sphingosine 1-phosphate receptor modulator. S1PR controls the release of
lymphocytes from lymph nodes and thymus and their penetration into CNS. S1PR is
also expressed on neurons and influences neurodegeneration and gliosis.
Use: orally administered for MS, Siponimod as orphan drug registered for
dermatomyositis and polymyositis
Adverse effects: headache, GI disorders, cardiac SE: AV block, QT prolongation
Ozanimod is in clinical trials for UC
Glatiramer acetat
not on the list
It is a standardized mix of polypeptides containing L-Alanin, L-glutamate, LLysine, L-Tyrosine – it is similar to myelin basic protein.
It competes with binding of MBP on MHC molecules and hereby antigen
presentation. It induces GA specific regulatory Th2 cells and neurotrophic factors.
It is used sc. for MS
Adverse effects: skin reactions on injection site, flush, diarrhea
Thalidomid
not on the list
It inhibits angiogenesis, TNFα secretion and activates IL-10 secretion. Blocks neutrophil functions as well.
Mainly used for multiplex myeloma and for erythema nodosum leprosum treatment. Off label sometimes used for SLE.
Apremilast (roflumilast)
cPDE4 Inhibitors. cAMP – PKA pathway is
anti-inflammatoric.
Roflumilast used for COPD, Apremilast for
psoriatic arthritis (see COPD)
and plaque psoriasis registered
AE: nausea, diarrhea, headache, respiratory
infection)
interferons
Type I Interferons (α subtypes and β Inf) are part of the innate immune system.
They use common receptors, and could have also immunosuppressive functions.
Use: Inf-α subtypes are used for viral infections and for tumor therapy. Inf-β-1a and 1b are used in remitting relapsing MS (3 times a week sc.) Inf-β-1a is also available
in pegylated form and given in every two weeks.
Adverse effects: flu like symptoms (fever, tiredness, muscle pain etc.), suppression of BM, GI disorders, disturbance of liver and kidney function, CNS problems, etc.
Inf-γ is used as an immune stimulant in chronic granulomatosis.
