Recent Advances In The Treatment Of Sle

RECENT ADVANCES IN THE TREATMENT OF SLE 1. THALIDOMIDE: Nature of drug: It is a non polar glutamic acid derivative MOA:  It causes specific inhibition of TNF-alpha. It also suppresses IL-12 which has a crucial role in the development 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 most patients. (B) SLE --------- useful for only cutaneous manifestations, not effective for systemic involvement in SLE. MOREOVER, NEEDS HIGHER DOSE FOR LONGER PERIODS. 2. METHOTREXATE: MOA:

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It interferes with folic acid synthesis by rapid (within 1 hour) irreversible binding to the enzyme dihydrofolate reductase which prevents the formation of tetrahydrofolic acid. The resultant inhibition of folate dependant enzymes such as thymidilate synthase or AICART (aminoimidazolecarboxamide ribonucleotide transformylase) compromises with purine synthesis required for DNA, RNA and protein synthesis. By this mechanism it may directly inhibit epidermal cell proliferation as well as multiplication of lymphocytes necessary for inflammation. The drug acts in the S phase of the cell cycle. Inhibition of AICART leads to intracellular accumulation of AICAR and release of adenosine into extracellular space. This causes inhibition of PMNL and retards the secretion of TNF-alpha, IL-6 and IL-8 by 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, reduces overall 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 : 

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CyCLOSPORINE AND TACROLIMUS mainly affect the T lymphocytes. Here it inhibits the production of IL-2 (T cell growth factor) by activated CD4+ T cells. Due to this there is reduced numbers of activated CD4 and CD8 T cells in the epidermis. Cyclosporin also inhibits T cell production of cytokines such as IFN – gamma (which promotes the release of proinflammatory cytokines by keratinocytes also, IFN- gamma is known to increase the expression of ICAM-1 that is important for leucocyte traffic into the skin). Thus inflammation is reduced. May also affect other cells like APCs and mast cells. CYCLOSPORINE

USE 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 is effective especially in pure lupus membranous nephritis.  It is used in refractory lupus nephritis cases who have failed to respond to other treatment modalities as the last resort. TACROLIMUS USE IN LE:  DOSE ------------ 0.11 mg/kg/day  Same indications like cyclosporine. 4. RETINOIDS

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 also occurs in hyperkeratotic variety of DLE. 5. MYCOPHENOLATE MOFETIL: MOA:  The active drug is mycophenolic acid. It is a non competitive inhibitor of inosine monophosphate dehydrogenase. Due to the inhibition of this enzyme, there is depletion of intracellular GUANINE nucleotide pools, reducing the substrates for DNA polymerase.  Lymphocytes rely on this pathway solely ----- therefore are most affected. There is reduction of antibodies 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 IMMUNOGLOBULIN It is extracted from pooled plasma requiring between 10,000- 20,000 donors per production cycle. It is composed primarily of IgG class. IgA is eliminated as much as possible to decrease the possibility of anaphylaxis. Peak plasma levels are reached almost immediately . serum levels drop between 40-50% of their peak within 1 week of administration. 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 to depletion of intracellular pyrimidine and failure to synthesize DNA or RNA in response to stimuli resulting in inhibition of 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) relative increased intracellular production of the active metabolite through deoxycytidine kinase and slow degradation secondary 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 Anti IL-10

MOA Counters the increased IL-10 in SLE.

dose For 21 days .

Rituximab

Directed against CD20 molecules on B cells

375 mg/sq. m . in weekly infusion.

Tocilizumab

Directed against IL-6 receptor.

Biweekly infusions for 12 weeks

Abetimus sodium

It induces tolerance in B cell directed against double stranded DNA.

CM-T412

Anti CD4 antibody

100 mg for 16 weeks followed by 8 wks of drug holiday and 12 weekly dose of 50 mg Given in 2 cycles of 1 and 4 infusions of 25 mg daily separated by 4-7 weeks

Effect Cutaneous lesions and joint symptoms improved . eventually patients developed antibodies to the drug. Used successfully in SLE patients with renal or CNS disease. Also used for chronic remission maintenance therapy. When used in mild to mod. SLE, it decreased both activated B and T cells. Reduced renal failure. Effects on cutaneous manifestations under trial.

There was an immediate response in all patients with near complete loss of cuatenous inflammatory activity by the end of each cycle. Responsiveness to conventional immunosuppressive therapy retained

after treatment. 10. PLASMA EXCHANGE It 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 threatening manifestations and severe therapy resistant manifestations like refractory SLE renal disease, diffuse alveolar hemorrhage, 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, reduced the 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 AND IMMUNOSUPPRESIVES): 1. THALIDOMIDE In scleroderma, the T helper (Th2) type of immune response is predominant. Thalidomide on the other hand, stimulates Th1 type of cellular response. By this immune manipulation ------------ it serves to be effective in systemic sclerosis. 2. INTERFERONS: BASIS OF ITS USE IN SYSTEMIC SCLEROSIS ---------Inhibits Th2 cytokines like IL-4, IL-5 and IL-6 -------- these CYTOKINES are responsible for fibroblast chemotaxis and proliferation ----- collagen production. The elevated collagen production in scleroderma, morphea, fibroblasts has been inhibited by IFN-alpha, beta and gamma. The inhibition does not PERSIST. In a study to assess the clinical and therapeutic efficacy of RECOMBINANT IFN-GAMMA ------------ it was given daily im for 6 months. Escalating doses of IFN-gamma initially at 10 mcg/day were administered and patients achieved a constant dose of 100 mcg/day for final 5 months of the study. Significant improvements from the baseline values was observed in total skin thickening score, maximal oral opening, range of wrist and elbow movements, grip strength, functional index, dysphagia and Creatinine clearance. The results were promising. 3. PAMIDRONATE BASIS FOR ITS USE IN SYSTEMIC SCLEROSIS ---------It is a bisphosphonate that inhibits bone resorption and is indicated primarily for the treatment of hypercalcemia associated with malignancy as well as for bone metastasis and Paget’s 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 blocks transforming growth factor beta over expression of type I and II procollagens, increases the over expression of matrix metalloproteinase and reduces the production of tissue inhibitor of metalloproteinase. Administered as continuous SC infusion of 25-100 microgram/kg for 24 weeks. Improvement was observed in shin tightness and pulmonary functions. ADR: Menometrorrhagia, reversible anemia, irritation and focal infections at the site of injection. 5. EXTRACORPOREAL PHOTOPHERESIS -----It is regarded as a immunotherapy in which a small portion of the peripheral 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 and individual treatment session takes 3 to 31/2 hours. It is performed after ingestion of 8-MOP. To achieve therapeutic index of the drug, patients are needed 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.

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STEM CELL TRANSPLANTATION ---- it is a treatment in which we take either the patients own cells or a close relatives cells and give them back to the patient after the patient’s immune system has been removed as much as possible. The idea is that one removes the cells that are doing harm and allows a new immune system 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 patient’s own cells (ie. Autologous) Only patients with the most progressive disease where the disease duration is more than 3 years are selected for this procedure which is found to significantly improve the QOL and longevity.

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

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UROKINASE THERAPY ----- It is a fibrinolytic enzyme isolated from human urine, now prepared from cultured human kidney cells. It activates plasminogen directly and has a plasma half life of 10-15 minutes. Studies have found that there is gradual improvement of Raynaud’s phenomenon and articular symptoms. EM findings show 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 increases RBC deformability. NEFIDIPINE IS THE AGENT OF CHOICE IN RAYNAUD’S PHENOMENON. Its dose is 10 mg three times 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 and platelet aggregation. Dose is 40 mg TDS. (3) SSRI ---- Fluoxetine decreases platelet 5-HT which is thought to play a role in the pathogenesis of Raynaud’s phenomenon. Dose is 20 mg daily. (4) ANGIOTENSIN ANTAGONIST ---- Losartan is a competitive inhibitor of angiotensin II and is more selective for AT1 than AT2 receptor. It blocks all overt actions of angiotensin II viz. vasoconstriction, central and peripheral 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 and activation. IT HAS BEEN USED SUCCESSFULLY BOTH AS SINGLE AGENT AND COMBINATION THERAPY FOR TREATMENT OF RAYNAUD’S PHENOMENON. DOSE --------- 400 mg three to four times daily. (6) NITRIC OXIDE DONORS ---- Topical nitroglycerine paste (2%) and a sustained release transdermal glyceryl patch 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, reduces platelet aggregation, alters neutrophilic function including free radical formation and promotes endothelial cell lining. It also promotes production and release of profibrotic cytokine, CT growth factor from fibroblasts thus lessening its concentration in sclerodermatous skin. The drug is administered as 5-10 day infusion (1-10 ng/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 Raynaud’s phenomenon. In addition to widening blood 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 patient’s with Raynaud’s phenomenon. (11)XANTHINOL NICOTINATE --- it is a compound of xanthine and nicotinic acid both of which are vasodilators. It increases 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 to cause peripheral vasodiation when given IV. Leads to healing of digital ulcers. DOSE --- A total of 100 mcg daily 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 and cardiopulmonary hemodynamics. (2) ILOPROST ---- also used for pulmonary hypertension where there is decrease of pulmonary vascular resistance --- 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. In addition, 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 responses through the interaction with CD2 receptors ---------- it prevents activation of T lymphocytes. With weekly IV infusions, 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 and because of its antibacterial properties. Few patients showed improvement in CALCINOSIS AND FINGER ULCERATIONS RELATED TO CALCINOSIS.

(2)

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