B-30. Pharmacotherapy of autoimmune diseases. Flashcards
The role of Th1, Th2, Th17, and Tregs
What inflammatory pathway does RA, IBD, and psoriasis most likely share?
Th-17 T-lymphocyte pathway
How does the AI chronic inflammation most likely occur
Surface damage leads to appearance of antigens in the tissue present by APC. APC induce CD4+ T-cell by IL-6 and IL-23 and directly inducing neutrophils via IL-1
Treatment goals of RA
- Slow down inflammation process (achieve remission)
- Relieve symptoms
- Prevent joint and organ damage
- Improve physical function and overal well being
- Reduce long-term complications
Treatment options in RA
- Conventional synthetic disease modifying antirheumatic drugs (CsDMARDs) as soon as possible:
- Methotrexate (first option)
- Alternatives cytotoxic drugs
- short term, tapered glucocorticoid or local steroids
- If necessary: add biological and so-called targeted synthetic DMARDs
- In case of ineffeciency other biological and tsDMARDS can be used
Alternative csDMARDs used in RA
- Leflunomide
- Sulfasalazine
- Chloroquine
- Cyclosporin-A
- Cyclophosphamide
- Azathioprine/6-mercaptopurine
Non DMARDs used in RA
- NSAIDs
- Corticosteroids
NSAIDs are used in RA to? Long term issues?
- They are also essential in the treatment but only symptomatic: they improve the symptoms, but do not slow the progression (even they could facilitate it)
- Long term issues are
- GI ulcerations
- Cardiovascular risk in RA increased- COX2 inhibition could worsen it
Corticosteriod use in RA? Dosing?
- In acute exacerbation they are the most effective drugs
- They can also suppress the progression
- Dosing
- High dose (transient treatment)
- Low dose (maintained treatment)
- Intraarticular local treatment is also used
RA treatment algorithm phase I
- Start methotrexate
- +Combine with short term glucocorticoids
- Start Leflunomide or sulfasalazine
- If the patient goes into remision then lower dose
- If patient doesn’t go into remission, go to phase II
RA treatment algorithm phase II
- Prognostically unfavorable factors present (RF/CPA/high disease activity/early joint damage)
- Add a bDMARD or Jack inhibitor
- Prognostically unfavorable factors not present
- Change to or add a second conventional synthetic DMARD (Leflunomide, sulfasalazine, methotrexate)
Phase III of RA
- Change the bDMARD
- Abatacept
- IL-inhibitor
- Rituximab
- (second)TNF-inhibitor
- Or add a Jak-inhibitor
Biologics used in treatment of RA
- TNF alpha antagonist (infliximab, adalimumab, certolizumab pegol, etanercept, golimumab)
- CTLA4- containing fusion protein (abatacept)
- IL-1 receptor antagonist (anakinra)
- IL-6 receptor antagonisst (tocilizumab, sailumab)
- CD20 antagonist (rituximab)
Targeted synthetic DMARDS
- Jak inhibitors
- Tofacinitib
- Baricitinib
Mild therapeutic approach of IBDs
- Mild
- 5-aminosalicylic acid (both in CD and UC)
- Locally applied 5-ASA and glucocorticoids
- Budesonide (both in CD and UC)
Moderate (or refractory to the mild form of IBD) treatment
- Moderate IBD treatment
- Oral glucocorticoids (both CD and UC)
- Azathrioprine/6-mercaptopurine (both in CD and UC)
- Methotrexate (CD)
Severe IBD treatment and if this fails what is next?
- Severe IBD treatment
- IV glucocorticoids
- TNFalpha antagonist (Infliximab, Adalimumab, Golimumab)
- Cyclosporine (UC)
- IL12/IL23 antagonist (Ustekinumab) (CD)
- Integrin antagonist (Natalizumab, Vedolizumab) (CD)
- If these treatments fail or in conjuncture with them you migh have to do surgery
Glucocorticoids in IBDs
- Usually short term treatment to avoid adverse effects
- If possible locally acting glucocorticoids (e.g. hydrocortisone enema) or drugs with high first pass metabolism (budesonide controlled release preparations) are preferred
- If necessary prednisolone (predenisonein theU.S.) per os o rmethylprednisolone (oral or injection) are given
Treatment goals in psoriasis
- Successful treatment: decrease in the psoriasis Area and Severity Index (PASI) score of 75% or greater
- Unsuccessful treatment: improveent is lower than 50% in the PASI score→change in the treatment
Drug classes treatments of psoriasis
- PUVA
- Topically applied drugs
- Systemically applied drugs
- Biologics
What is PUVA?
UV beam after taking 8-methoxypsoralene orally or applying a cream or bath. The drug makes the plaques photosensitive
Topically applied drugs in psoriasis
- Topically applied drugs
-
Glucocorticoid creams alone or with tar or Vit. D3 analogs
- calcipotriol with betamethasone (cream or gel)
- or tacalcitol emulsion
- Retinoids
- tazaroten
-
Glucocorticoid creams alone or with tar or Vit. D3 analogs
Vit. D analogs do what in psoriasis
Vitamen D analogs inhibit keratocyte proliferation, used only in localized plaque psoriasis
Systemically applied drugs in psoriasis
- Systemically applied drugs
- Acitretin
- Immunosuppresive drugs
- Cyclosporin
- Methotrexate
- Leflunomide
- Dimethyl-fumarate
- PDE-4 inhibitors
- Apremilast
- Biologicals
- More later
Acitretin in psoriasis
Inhibits synthesis of keratin precursors, decreases hyperkeratosis
Dimethyl-fumarate in psoriasis
Stimulates transcription factors
Apremilast (PDE-4 inhibitor) function in psoriasis
Inhibits expression of TNF-alpha, IL-23, IL-17, and other inflammatory cytokines
Mechanism of action and retinoid drugs used in psoriasis
- MOA: Inhibition of cell proliferation and differentiation (they bind to nuclear retinoid receptor RAR and/ or RXR)
- Drugs
- Tazaroten (locally applied)
- Acitretin (systemic)
Acitretin (systemic) use, adverse effects
- Can be used in more severe psoriasis
- Adverse effects may include…
- Dry mucosa (e.g. xerophtalmia=dry eyes)
- Iitching
- Several skin problems (e.g. hairloss, exfoliation, dermatitis, pyogen granuloma)
- Extremely teratogenic-!!! Getting pregnant must be avoided duringand 3 years after terminating the treatment!!!
Biologics used in the treatment of psoriasis
- L-23R antagonists
- ustekinumab (IL-12R/IL-23R), guselkumab, risankizumab
- IL-17 antagonists
- ixekizumab, secukinumab
- IL-17R antagonist
- brodalumab
- TNFalpha antagonists
- adalimumab, etanercept, infliximab
Therapy of mild atopic dermatitis
- Therapy depends on severity
- Mild form
- Local creams (emollients, pimecrolimus, glucocorticoids)
- Systemic steroids only in acute exacerbation for a short time
- Mild form
Therapy for more severe forms of atopic dermatits
- More severe forms: systemic drugs
- Cyclosporin-A
- Or IL4R/IL3R antagonist dupilumab
Treatment options in MS classes
- Interferons
- Glatiramers
- Antimetabolites
- Leukocyte depletion
- T-cell inhibition
- B-cell depletion
- Other (dimethyl-fumarate)
- Improving motoric functions
Which interferons are used in in MS
- INF-B1a
- INF-B1b
Glatiramers are
Mixture of short peptides corresponding myelin building blocks
Antimetabolites drugs? how are they taken?
- Taken orally
- Drugs
- Teriflunomide (dihyroorotate-dehydrogenase inhbitor)
- Cladribine (purine analog)
Leukocyte depletion drug
- Alemtuzumab- CD53 inhibitor, T and B cell depletion, IV induction treatment
Other treatments in MS
- Orally taken Dimethyl-fumarate
- Nuclear factor (erythroid derived 2)-like 2 (Nrf2) transcription pathway stimulator- increases the level of antioxidant enzymes
MS drugs improving motoric function
- Fampridine (4-aminopyridine)- K+-channel blocker
