recent advances in the treatment of sle

8/14/2019 Recent Advances in the Treatment of Sle

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RECENT ADVANCES IN THE TREATMENT OF SLE

1. THALIDOMIDE:Nature of drug: It is a non polar glutamic acid derivativeMOA:

It causes specific inhibition of TNF-alpha. It also suppresses IL-12 which has a crucial role in thedevelopment of cellular immunosuppression

Antiinflammatory -------- it decreases neutrophils and monocyte chemotaxis and phagocytosis. It

antagonizes the inflammatory mediators ---------- histamine, prostaglandins and 5- HT.

Use in LE:(A) In CCLE AND SCLE --------- they respond to smaller initial dose (50-200 mg/day) and the response is usually

seen in 2-3 weeks. Thereafter the dose can be reduced to a maintenance of 25-50 mg/day for mostpatients.

(B) SLE --------- useful for only cutaneous manifestations, not effective for systemic involvement in SLE.MOREOVER, NEEDS HIGHER DOSE FOR LONGER PERIODS.

2. METHOTREXATE:MOA:

It interferes with folic acid synthesis by rapid (within 1 hour) irreversible binding to the enzymedihydrofolate reductase which prevents the formation of tetrahydrofolic acid. The resultantinhibition of folate dependant enzymes such as thymidilate synthase or AICART (aminoimidazole-

carboxamide ribonucleotide transformylase) compromises with purine synthesis required for DNA, RNAand protein synthesis. By this mechanism it may directly inhibit epidermal cell proliferation as well asmultiplication of lymphocytes necessary for inflammation. The drug acts in the S phase of the cellcycle.

Inhibition of AICART leads to intracellular accumulation of AICAR and release of adenosine intoextracellular space. This causes inhibition of PMNL and retards the secretion of TNF-alpha, IL-6 and IL-8by histiocytes. This is responsible for the antiinflamatory effects of methotrexate.

It can also suppress primary and secondary antibody responses.

It also reduces SAM (S-adenosyl methionine) production, a proinflammatory mediator.

Use in LE:

In steroid resistant cases but without renal and CNS involvement.

At a dose of 10-20 mg/week, it is useful for mucocutaneous lesions, improves the articular symptoms, reducesoverall disease activity and exerts a steroid sparing effect.

It does not have a promising role in life threatening renal and CNS involvement.

3. CALCINEURIN INHIBITORS (cyclosporine and tacrolimus)They cause immunosuppression primarily through suppression of T cell activation.

MOA :

CyCLOSPORINE AND TACROLIMUS mainly affect the T lymphocytes. Here it inhibits the production ofIL-2 (T cell growth factor) by activated CD4+ T cells. Due to this there is reduced numbers of activatedCD4 and CD8 T cells in the epidermis.

Cyclosporin also inhibits T cell production of cytokines such as IFN gamma (which promotes therelease of proinflammatory cytokines by keratinocytes also, IFN- gamma is known to increase theexpression of ICAM-1 that is important for leucocyte traffic into the skin). Thus inflammation isreduced.

May also affect other cells like APCs and mast cells.

CYCLOSPORINEUSE IN LE:

The dose in 3-5 mg/kg/day

Discoid erythema, malar rash, photosensitivity, cutaneous vasculitis improved.

In lupus nephritis, there is a reduction in overall disease activity and steroid sparing effect. It iseffective especially in pure lupus membranous nephritis.

It is used in refractory lupus nephritis cases who have failed to respond to other treatment modalitiesas the last resort.

TACROLIMUSUSE IN LE:

DOSE ------------ 0.11 mg/kg/day

Same indications like cyclosporine.

4. RETINOIDS


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Synthetic Vitamin A analogues such as isotretinoin, etretinate and acitretin (in a dose of 1 mg/kg/day)have been demonstrated to be highly effective in the treatment of refractory SCLE lesions. A good response alsooccurs in hyperkeratotic variety of DLE.5. MYCOPHENOLATE MOFETIL:MOA:

The active drug is mycophenolic acid. It is a non competitive inhibitor of inosine monophosphatedehydrogenase. Due to the inhibition of this enzyme, there is depletion of intracellular GUANINEnucleotide pools, reducing the substrates for DNA polymerase.

Lymphocytes rely on this pathway solely ----- therefore are most affected. There is reduction ofantibodies and inflammatory cytokines.

USE IN LE:(1) It is specially beneficial in LUPUS NEPHRITIS. DOSE ---------- 0.5-2gm daily. There is overall reduction in SLE

disease activity index and significant reduction in steroid dose.(2) Cutanoeus lesions also improve after 2-4 weeks treatment.

6. INTRAVENOUS IMMUNOGLOBULINIt is extracted from pooled plasma requiring between 10,000- 20,000 donors per production cycle. It is composedprimarily ofIgG class. IgA is eliminated as much as possible to decrease the possibility of anaphylaxis. Peak plasmalevels are reached almost immediately . serum levels drop between 40-50% of their peak within 1 week ofadministration. The half life is 3-5 weeks.

MOA:

Blockade of RES receptor

Impedence of complement mediated lysis

Reduction of circulating autoantibodies

Alteration of cytokine profile.

USE IN LE:There is improvement in lupus nephritis and cutaneous lesions but the effect is short lasting (4-6 weeks). Dose:

2 gm/kg/month divided in five doses of 0.4 gm/kg/day.

7. LEFLUNOMIDE (lymphocyte specific pyrimidine antagonist)MOA: The active metabolite of this drug inhibits the enzyme DIHYDROOROTATE DEHYDROGENASE, leading todepletion of intracellular pyrimidine and failure to synthesize DNA or RNA in response to stimuli resulting in inhibitionof cell cycle progression. In LE there is significant reduction of overall disease activity.DOSE: 100mg/day for 3 days then 20 mg/day for maintenance.

8. NUCLEOSIDE ANALOGUES (CLADRIBINE, CYTARIBINE and FLUDARIBINE)MOA: they are selective lymphocyte depleting agents. This selectivity is conferred by two mechanisms ------ (i) relativeincreased intracellular production of the active metabolite through deoxycytidine kinase and slow degradationsecondary to limited nucleotidase within mononuclear cells. CUATNEOUS MANIFESTATIONS RESPOND WELL BUT

EFFECT IS SHORT LASTING.

CLADRIBINE ------------ USED AS continous 7 days infusion of 0.5 mg/kg/day.CYTARIBINE -------------- dose is 2 mg/kg/day for 5 days every 4 weeks for 3 courses.

9. BIOLOGICAL AGENTS:

Drug MOA dose EffectAnti IL-10 Counters the increased IL-10 in

SLE.For 21 days . Cutaneous lesions and joint

symptoms improved . eventuallypatients developed antibodies to thedrug.

Rituximab Directed against CD20 moleculeson B cells

375 mg/sq. m . inweekly infusion.

Used successfully in SLE patients withrenal or CNS disease. Also used for

chronic remission maintenancetherapy.Tocilizumab Directed against IL-6 receptor. Biweekly infusions

for 12 weeksWhen used in mild to mod. SLE, itdecreased both activated B and Tcells.

Abetimussodium

It induces tolerance in B celldirected against double strandedDNA.

100 mg for 16 weeksfollowed by 8 wks ofdrug holiday and 12weekly dose of 50mg

Reduced renal failure. Effects oncutaneous manifestations under trial.

CM-T412 Anti CD4 antibody Given in 2 cycles of 1and 4 infusions of 25mg daily separatedby 4-7 weeks

There was an immediate response inall patients with near complete loss ofcuatenous inflammatory activity bythe end of each cycle.Responsiveness to conventionalimmunosuppressive therapy retained


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after treatment.

10. PLASMA EXCHANGEIt can remove pathogenic antibodies an circulating immune complexes from the blood of patients with SLE.Plasmapheresis of 2 litre/day for 3-4 days each week over a period of 3-4 weeks is indicated in acute life threateningmanifestations and severe therapy resistant manifestations like refractory SLE renal disease, diffuse alveolarhemorrhage, neuropsychiatric SLE, TTP, catastrophic antiphospholipid syndrome, cryoglobulinemia.

Benefit lasts only approximately 2-3 weeks.11. PHOTOTHERAPY (UVA1 phototherapy)

UVA1 (340-400 nm) at a dosage of 60 kJ/sq.m three times weekly reduced disease activity, reducedthe need for medications and decreased antibody levels.

OTHER DRUGS MENTIONED ---------

CYCLOPHOSPHAMIDE AZATHIOPRINE

DAPSONE

RECENT ADVANCES IN THE TREATMENT OF SYSTEMIC SCLEROSIS

DRUGS to DECREASE SCLEROSIS IN SYSTEMIC SCLEROSIS (BESIDES STEROIDS ANDIMMUNOSUPPRESIVES):1. THALIDOMIDE

In scleroderma, the T helper (Th2) type of immune response is predominant. Thalidomide on the otherhand, stimulates Th1 type of cellular response. By this immune manipulation ------------ it serves to be effective insystemic sclerosis.2. INTERFERONS:

BASIS OF ITS USE IN SYSTEMIC SCLEROSIS ---------Inhibits Th2 cytokines like IL-4, IL-5 and IL-6 -------- theseCYTOKINES are responsible for fibroblast chemotaxis and proliferation ----- collagen production. The elevatedcollagen production in scleroderma, morphea, fibroblasts has been inhibited by IFN-alpha, beta and gamma. Theinhibition does not PERSIST.

In a study to assess the clinical and therapeutic efficacy of RECOMBINANT IFN-GAMMA ------------ it wasgiven daily im for 6 months. Escalating doses of IFN-gamma initially at 10 mcg/day were administered andpatients achieved a constant dose of 100 mcg/day for final 5 months of the study. Significant improvements fromthe baseline values was observed in total skin thickening score, maximal oral opening, range of wrist and elbowmovements, grip strength, functional index, dysphagia and Creatinine clearance. The results were promising.3. PAMIDRONATEBASIS FOR ITS USE IN SYSTEMIC SCLEROSIS ---------It is a bisphosphonate that inhibits bone resorption and isindicated primarily for the treatment of hypercalcemia associated with malignancy as well as for bone metastasisand Pagets disease.

It has immunomodulatory properties acting as a ligand for a subset of T cells that express gamma-delta

T cell receptor. When this subclass of T cells is activated by pamidronate, an alteration of cytokine pattern occurs----------- there is increase in the production of interferon gamma ------------ inhibits collagen production.

4. RECOMBINANT HUMAN RELAXIN ---------- it is a pregnancy polypeptide, cytokine growth factor which blockstransforming growth factor beta over expression of type I and II procollagens, increases the over expression ofmatrix metalloproteinase and reduces the production of tissue inhibitor of metalloproteinase. Administered ascontinuous SC infusion of 25-100 microgram/kg for 24 weeks. Improvement was observed in shin tightnessand pulmonary functions. ADR: Menometrorrhagia, reversible anemia, irritation and focal infections at the siteof injection.

5. EXTRACORPOREAL PHOTOPHERESIS -----It is regarded as a immunotherapy in which a small portion of theperipheral lymphocyte pool (less than 5%) is isolated, photochemically altered and then reinfused.

Currently ECP machines are available to perform the task. It can be done as an OPD procedure andindividual treatment session takes 3 to 31/2 hours.

It is performed after ingestion of 8-MOP. To achieve therapeutic index of the drug, patients areneeded to ingest 0.6-0.8 mg/kg 1.5 hours before treatment. Procedure is shown in diagram. The treatment is typically

repeated on the second day and this 2 day cycle is repeated monthly.MOA:(A) Stimulation of anti-T (tumor) cell immune responses(B) Induction of apoptosis of activated T cells(C) Induction of immunoregulatory cytokine shift.

In systemic sclerosis ECP can cause reversal of skin changes as well as stopping progression of skin involvement.

6. STEM CELL TRANSPLANTATION ---- it is a treatment in which we take either the patients own cells or aclose relatives cells and give them back to the patient after the patients immune system has been removedas much as possible. The idea is that one removes the cells that are doing harm and allows a new immunesystem to develop. The new immune system sees scleroderma as normal and does not react against itself.Currently most stem cell transplantation for systemic sclerosis has been done with patients own cells (ie.Autologous)

Only patients with the most progressive disease where the disease duration is more than 3 years areselected for this procedure which is found to significantly improve the QOL and longevity.


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THE PROCESS ------- Stem cells circulating in the blood in small numbers are removed ------- this is calledMOBILIZATION. After that high dose immunosuppressive therapy sometimes combined with proteins and/orradiation therapy which kills the immune cells is used to get rid of the bodys abnormal immune system ----------this is called CONDITIONING. Finally medicines are given to stimulate the new cells for faster recovery.

7. UROKINASE THERAPY----- It is a fibrinolytic enzyme isolated from human urine, now prepared from culturedhuman kidney cells. It activates plasminogen directly and has a plasma half life of 10-15 minutes. Studieshave found that there is gradual improvement of Raynauds phenomenon and articular symptoms. EM findingsshow that after treatment the collagen fibres appeared to have a more regular diameter.

VASCULAR THERAPIES IN SYSTEMIC SCLEROSIS----Depend on 3 modalities ------------ (1) Non pharmacologic (2) Pharmacologic and (3) Surgery

Pharmacologic therapies -----(1) CALCIUM CHANNEL BLOCKERS ------- Nefidipine, Diltiazem, Amlodipine. Prevent calcium influx for smooth

muscle contraction ----- therefore resulting in vasodilation. It also inhibits platelet aggregation and increasesRBC deformability. NEFIDIPINE IS THE AGENT OF CHOICE IN RAYNAUDS PHENOMENON. Its dose is 10 mg threetimes daily or 20 mg twice daily of susyained release preparations upto a maximum of 90 mg daily.

(2) KETANSERIN --- It blocks serotonin receptora and thereby inhibits serotonin induced vasoconstriction andplatelet aggregation. Dose is 40 mg TDS.

(3) SSRI ---- Fluoxetine decreases platelet 5-HT which is thought to play a role in the pathogenesis of Raynaudsphenomenon. Dose is 20 mg daily.

(4) ANGIOTENSIN ANTAGONIST ---- Losartan is a competitive inhibitor of angiotensin II and is more selectivefor AT1 than AT2 receptor. It blocks all overt actions of angiotensin II viz. vasoconstriction, central andperipheral stimulation. Dose is 50 mg OD.

(5) PENTOXYPHYLLINE ---- it is a methyl xanthine derivative. MOA ---- it increases both RBC and leukocyte

deformability and inhibits neutrophil adhesion and activation. It also reduces platelet aggregation andactivation. IT HAS BEEN USED SUCCESSFULLY BOTH AS SINGLE AGENT AND COMBINATION THERAPY FORTREATMENT OF RAYNAUDS PHENOMENON. DOSE --------- 400 mg three to four times daily.

(6) NITRIC OXIDE DONORS ---- Topical nitroglycerine paste (2%) and a sustained release transdermal glycerylpatch may improve local blood flow by releasing nitric oxide that induces vasodilation.

(7) ILOPROST ---- it is a chemically stable prostacyclin agonist. It produces prolonged vasodilation, reducesplatelet aggregation, alters neutrophilic function including free radical formation and promotes endothelial celllining. It also promotes production and release of profibrotic cytokine, CT growth factor from fibroblasts thuslessening its concentration in sclerodermatous skin. The drug is administered as 5-10 day infusion (1-10ng/kg/min) for 8 hours a day (a total dose of 5 lak ng daily. FORMULATION --- EPOPROSTENOL

(8) PROSTAGLANDINS ---- PGE1 is used for treatment of severe Raynauds phenomenon. In addition to wideningblood vessels, PGE1 can also protect vascular endothelial cells.

(9) BOSENTAN ---- the non selective ENDOTHELIN ANTAGONIST may be beneficial upon digital ischaemia and

may decrease the incidence of digital ulceration. DOSE --- 62.5 mg BD with dose escalation to 125 mg BID.(10)HEXYLNICOTINATE --- AVAILABLE AS 2% CREAM to be applied thrice daily -------- it has been shown to

increase blood flow when applied topically in patients with Raynauds phenomenon.

(11)XANTHINOL NICOTINATE --- it is a compound of xanthine and nicotinic acid both of which are vasodilators. Itincreases blood flow in many vascular beds. DOSE --- 300-600 mg TDS oral, 300 mg by IM or slow IV injection.COMPLAMINA is available as 150 mg tablet, 500 mg retard tablet and 300 mg/2 ml inj.

(12)CALCITONIN GENE RELATED PEPTIDE --- it is a potent endogenous vasodilator and has been shown tocause peripheral vasodiation when given IV. Leads to healing of digital ulcers. DOSE --- A total of 100 mcgdaily are given for 5 consequetive days at a infusion rate of 0.6 mcg/min for 3 hours daily.

DRUGS FOR PULMONARY COMPLICATION OF SYSTEMIC SCLEROSIS

(1) BOSENTAN ---- It is used in the treatment of pulmonary hypertension. It also improves exercise capacity andcardiopulmonary hemodynamics.

(2) ILOPROST ---- also used for pulmonary hypertension where there is decrease of pulmonary vascularresistance --- improvement of symptoms of right heart failure and exercise capacity.(3) CYCLOPHOSPHAMIDE ----it is used alone or in combination with low dose prednisolone in the treatment of

severe interstitial lung disease in SS. The dosage consisted of 1-1.5 mg/kg/day orally to UPTO 2 mg/kg/day. Inaddition, monthly pulse cyclophos 800-1400 mg is given for 6-9 months .

(4) ALEFACEPT ---- It is a recombinant protein that has been designed to modulate the immune responsesthrough the interaction with CD2 receptors ---------- it prevents activation of T lymphocytes. With weekly IVinfusions, the number of blood and BAL T lymphocytes and other inflammatory WBCs was reduced.

DRUGS FOR CALCINOSIS ----

(1) MINOCYCLINE ------ It was used because of its ability to bind to calcium and remove it from circulation andbecause of its antibacterial properties. Few patients showed improvement in CALCINOSIS AND FINGERULCERATIONS RELATED TO CALCINOSIS.


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(2) EXTRACORPOREAL LITHOTRIPSY---- Used to treat soft tissue calcifications in patients with systemicsclerosis. Sound waves are used to break up the calcium deposits. Deposits become small and disappeared 2weeks after the treatment.

recent advances in the treatment of sle

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