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:
 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 (aminoimidazole-
carboxamide 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 :
 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 MOA dose Effect

Anti IL-10 Counters the increased IL-10 in For 21 days . Cutaneous lesions and joint
SLE. symptoms improved . eventually
patients developed antibodies to the
drug.
Rituximab Directed against CD20 molecules 375 mg/sq. m . in Used successfully in SLE patients with
on B cells weekly infusion. renal or CNS disease. Also used for
chronic remission maintenance
therapy.
Tocilizumab Directed against IL-6 receptor. Biweekly infusions When used in mild to mod. SLE, it
for 12 weeks decreased both activated B and T
cells.
Abetimus It induces tolerance in B cell 100 mg for 16 weeks Reduced renal failure. Effects on
sodium directed against double stranded followed by 8 wks of cutaneous manifestations under trial.
DNA. drug holiday and 12
weekly dose of 50
mg
CM-T412 Anti CD4 antibody Given in 2 cycles of 1 There was an immediate response in
and 4 infusions of 25 all patients with near complete loss of
mg daily separated cuatenous inflammatory activity by
by 4-7 weeks 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.

6. 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.

7. 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.