Refractory Cutaneous Lupus

Dr Renu Saigal , MD, FICP,MAMS

Professor & Head, Department of Medicine,

JNU Medical College,Institute for Medical Science & Research

Center, Jaipur

IRACON 2016

Skin lesions in lupus

• Cutaneous manifestations develop in 59–85% of patients

with SLE (Autoimmunity Reviews 10 (2011) 685–692)

• Antedate systemic symptoms in 25% Lupus pts

• Prolonged or recalcitrant lesions :

Produce disfigurement

Psychosocial morbidity and occupational disability

Goal : Prevention of long-term skin sequelae

Refractory cutaneous Lupus - Definition

• Lesions which do not respond to :

• Strict photoprotection

• Topical therapy

• Systemic therapy with AM and CS

• R/O Concomitant common skin diseases unrelated to lupus

: acne vulgaris, herpes zoster, asteatotic eczema, cutaneous

fungal infections and drug eruptions. *

Classification of Lupus skin lesions

• Lupus lesions *

• Vascular lesions

• Non-Lupus, Non-Vascular lesions

Lupus Cutaneous Lesions

Acute

• Localized• Generalized• TEN like

Subacute

• Annular• Papulosquamous

Chronic

• Localized• Generalized• Hypertrophic/verrucous• Mucosal• Lupus Panniculitis/

profundus• Lupus Tumidus• Chilblain Lupus• Lichenoid DLE (DLE-

lichen planus overlap)

DLE

Combined risk 12.2%

SCLE & DLE SLE

Acute Localized Malar rash SCLE : Annular SCLE :Papulosquamou

sDLE Bullous Lupus Lupus tumidus

Chilblain lupus

LUPUS/ Pannicul

itis (Profun

dus)

Granular deposits of immune deposits in the basement membrane zone of lesional skin.

Lupus band test ( DIF)

DLE : Hydropic degeneration of the basal layer

SCLE : A

SCLE (B)Hydropic degeneration of the basal layer and apoptotic keratinocytes in the epidermis

SCLE : Mucin deposition in the dermis

Lupus profundus. Patchy lymphocytic infiltrates in the dermis and subcutaneous tissue

Bullous Lupus

Histopathology

Diagnosis of CLE

• Made by clinical and histologic findings.

• Serology and DIF are < helpful in making the diagnosis.

Assessment of CLE

• Revised Cutaneous Lupus Area and Severity Index(RCLASI ) (Arch

Dermatol 2012;148:479-84.)

Anatomical region

Morphological aspects Erythema

Scaling/hyperkeratosis

Edema/infiltration

Scarring/atrophy

Cutaneous lupus therapeutic interventions

The journal of Clinical & Aesthetic Dermatology

(January 2013.Volume 6. Number 1)

BelimumabUstekinumab

Patient Education –Photoprotection & others

• Avoid high sun exposure (beaches, snow, lakes), especially between 10 AM and

3 PM & equatorial regions

• Avoid medications ,halogen/fluorescent bulbs/ photocopier machines that may

cause photosensitivity

• Use sunscreens daily, whether it is cloudy or rainy , 2mg/cm2

• To be applied 30 to 60 minutes prior to exposure and should be reapplied

every two to four hours.

• SPF ≥ 50

Photosensitivity :

• > in fair skin pts & pts with + ve anti-Ro Ab

• Vit D3 Supplements 2k/d

Hydrocortisone 1% /MPS/ Fluocinolone acetonide 0.01% (Low-mid-potency CS )Should not be used for >2 wks

Triamcinolone acetonide Betamethasone valerate(Mid-potency CS )

Clobetasol propionate(High-potency CS)

Topical corticosteroids : (Best Pract Res Clin Rheumatol. 2005;19:767–784.)

Immunosuppresants – CS –Local/systemic

Bullous lesionsOral/ nasal ulcers

• Triamcinolone 0.1%

• Clobetasol 0.05%• Takes a few days

to weeks to act

Refractory localized DLE

• 2.5 to 10mg/ml triamcinolone (Semin Cutan Med Surg. 2001;20:14–26.)

• 0.1 ml ID inj with 30G needle

Systemic CSDose & AE

• Prednisone of 0.5–1.0 mg/ kg/ day/ can be tapered over 2–4 weeks (Journal of American Academy of Dermatology 2011;65(6):e195–213.)

• Increased risk of AVN so avoid in isolated CLE

AE of chronic topical CS : Atrophy, Telangiectasia ,Hypertrichosis, striae and depigmentation.

Topical therapy (Calcineurin inhibitors)

Tacrolimus

• 0.1% & 0.03%• Facial lesions –

Acute, non-hyperkeratotic oedematous, CLE lesions

Pimecrolimus Oint

• 1% oint• Regressed lesions in

2 small studies (J Am Acad Dermatol 2004; 51:407, Rheumatology (Oxford) 2005; 44:1564.)

• Better than tacrolimus : More lipophilic, higher epidermal affinity, lower penetration into the skin

Tacrolimus 0.3% Clobetasol prop

• > effective than 0.1% Tacrolimus (Clin Exp Dermatol. 2010;35:27–30.)

Advantage : No risk of skin atrophy .

CI Side effects : Transient burning, erythema, and irritation.

DBRCT20

patients with

tacrolimus 0.1%

ointment

Clobetasol propionate

0.05% ointment.

Efficacy of two equal [British Journal of Dermatology 2007;156(1):191–

2.].

Telangiectasia (61%)on CS side as early as 3 weeks

‘Black-box’ warningCI : Heightened risk of malignancy, although there is no evidence to suggest a causal relationship (Clinics in Dermatology 2010;28:52–6.)

Systemic therapies

Indications

Widespread/ highly inflammatory /

scarring disease

Refractory to topical treatments

Topical agents are typically continued as an adjunctive therapy with systemic therapy

HCQ• Dose :• < 6.5 mg/kg (Ideal

wt) / day to a maximum of 400 mg/day,

• < 400mg/day for pts < 61 kg.

CQ• Dose : 250mg

/day)• No more than

3.5–4.0 mg/ kg/ day to minimise retinal toxicity.

• > Potent & Toxic than HCQ

Quinacrine• Dose : 50 to

100 mg/day• > Effective• Lower risk of eye

damage

Onset of action : 6-12 weeks . Combination of quinacrine to HCQ or CQ found effective (Lupus 2009; 18:735 Dermatology 1994; 189:425)

CI : Pre-existing retinopathy, blood disorders and myasthenia gravis, G6PD deficiency. [ Journal of Clinical and Aesthetic Dermatology 2013;6(1):27–38.].

AE AM

Reduce the seizure threshold

Xerosis

Eruptions exanthematous or lichenoid

drug, urticaria

Blue–gray skin,nail & mm

hyperpigmentation,

GI upset, discoloration of the hair,

Myopathy, cardiomyopathy

Quinacrine : Can cause yellow

discolouration of skin, sclera and bodily

fluids & BM suppression.

Ocular Toxicity :

Toxic effects of HCQ are

associated with duration of

therapy but not with daily

dose or patient weight. (Arthritis Care Res (Hoboken).

2010;62(6):775784)

Smoking & CLE & HCQ therapy

• Smokers have worse active CLE & DLE (Lupus.2008;17(4):337347) Smoking & CLE

• Smokers are refractory to treatment with AM and other systemic therapies.

• (J Am Acad Dermatol. 2000;42(6):983987)

• (Archives of Dermatology 2012;148(3):317–22. ; Clinical and Experimental Dermatology 2012;37(4):327–34. [J Am Acad Dermatol 2000; 42:983.]

Cessation of smoking -Strongly

advised

HCQ levels in refractory CLEFrench multicentre prospective study

Monitor HCQ levels to be sure that refractoriness is not secondary to insufficient HCQ levels

Treatment failure - 569 ng/ml

Partial remission – 692 ng/ml

Complete remission – Mean HCQ level 910 ng/ml (p 0.005)

300 patientsDLE 160,SCLE 86,LET 52 ChL 26,LP16

Acitretin 50mg/d n=28

Marked improvement or clearing of erythema in 10/24 patients (42%),

of infiltration in 15/24 (63%) and of scaling/hyperkeratosis in 12/20

(60%)

Overall improvement :13/28 patients (46%)

Relapses & AE : > in Acitretin

HCQ 400mg/dn = 30

Marked improvement of erythema in 17/25 patients (68%),

of infiltration in 17/25 (68%) and of scaling/hyperkeratosis in 15/23 (65%).

Overall improvement :15/30 patients (50%) with

HCQ

A RDBT multicentre study to compare the efficacy in CLE (8week study)

Methotrexate

• 7.5 Mg – 25 mg/d • Lesions clear in 6-8 weeks• Remission even after discontinuation

Dose

• 43 treatment-refractory CLE (esp in SCLE & DLE ) patients showed improvement in 98% of cases (British Journal of Dermatology 2005;153(1):157–62.)

Evidence

• 12 pts (6 SCLE, 4 DLE, 1 lupus panniculitis, 1 chilblain lupus)

• 10 showed response after 6 wks.• 5 had long term remission 5-24mths

following therapy

Retrospective study

12 pts to refr AM &CS

(Rheumatol Int 1998;18:59-62)

Mycophenolate mofetil and Mycophenolate sodium

• Effective in treating all CLE sub-types• (British Journal of Dermatology 2007;156(6):1321–7. J Am

Acad Dermatol. 2001;45(1):142.; Arch Dermatol2002;138(12):1616. ; Br J Dermatol. 2002;147(1):174.)

Indications

• 1-3 g /d • Response in 1-2 mths (J Am Acad Dermatol.

2011;65:e179–e213.)Dose

• Reversible cytopenias,GI toxicity• Hepato,reno toxicity -Monitor• Teratogenicity

Adverse events

Dapsone

• Highly inflammatory lesions of CLE• Bullous LE, Lupus panniculitis,SCLE &

DLEIndications

• 25- 200 mg/d• 55 CLE pts – 35% showed improvement

• [Current Rheumatology Reports 2011;13(4):300–7.] Dose

• Hemolysis (G6PD def)• agranulocytosis• Methaemoglobinaemia• PN -M• DRESS

Adverse events

Dose Dependent> In 1st three mths

• Recalcitrant Chronic & Subacute CLE• Ineffective in lupus panniculitisIndications

• 50-100mg/d , OA within 1 mth • Taper after clinical response -25-

50mg/d to 25-50 mg every three daysDose

• Irreversible PN –S M (within 1st yr) Taper dose if no improvement - stop

• Thrombosis, sedation,neutropenia, Sec Amenorrhoea,constipation

Adverse events

Thalidomide

1983 - 60 cases of chronic DLE (Br J

Dermatol. 1983;108:461–466.)

• 50 to 100mg/day• CR /PR - 90% • Relapse –in 71%

successfully treated patients following discontinuation

• 39% responded well to a second course

• PN(25%)

A 2005 study of 48 patients (Am J Med.

2005;118:246–250.)

• Diff doses• CR/PR :60% + 21%• No response 19%• Relapse in67%

(following discontinuation )who had attained CR/PR.

• 27% Pts PN non-dose-dependent

2011 -60 pts (42%DLE, 30%SCLE,

LE Profundus)* (Br JDermatol. 2012;166:616–623.)

• 100mg/d• CR/PR - 85%

+14%• No response in 1• Relapse in 70%• PN (18%)• 7pts had sec

amenorrhoea• *Unresponsive to

AM,IS

Thalidomide should be used as a short term remission-inducing agent.

Azathioprine

• Extensive or recalcitrant DLE

• [Arch Dermatol.1985;121(10):1323. Arch Dermatol. 1986;122(4):376. J Am Acad Dermatol. 1988;19(5 Pt 2):961.]

Indications

• 1 to 2.5 mg/kg/day of azathioprine. (N-TPMT )

• Improvement occurs within 1-2 months [J Am Acad Dermatol. 2002;46(4):600.].

Dose & OA

Lenalidomide

• 86% achieved complete response• Clinical relapse was frequent (75%) usually occurring 2 to 8 weeks after lenalidomide’s withdrawal.(Journal of American Academy of Dermatology 2012;66(4):571–82.) (Arthritis Research and Therapy 2012;14(6):R265.) (Archives of Dermatology 2009;145(3):303–6.)

Clofazimine

• 100 or 200 mg/day for 3-6 months.

• Remission occurred in (65 percent).

• 6 patients remained in remission 2-5 months after treatment was discontinued.

Uncontrolled study of 26 pts of DLE where CQ

& Other trt failed [Br J Dermatol.1974;91(1):93.].

Clofazimine

• DBRT & over 6 month pd : (www.nature.com/clinicalpractice/rheum JANUARY 2006 VOL 2 NO 1)

16 pts active SLE on CLFZ

(100mg/d )

Responders 75%

5 pts had flare &

withdrew

17 pts on CQ (250mg/d)

Responders82.4%

1pt withdrew

Biologics

• Severe,extensive,refractory CLE ,efficacy in 74% pts CLE (French AutoImmunity and Rituximab registry. Arthritis Rheum. 62,2458–2466 (2010).

• In case reports efficacy shown [Journal of American Academy of Dermatology 2011;65(6):e195–213] Rheumatology. 2006;45:915–916.Australas J Dermatol. 2009;50:202–206.Dermatology. 2008;216:257–259

• Mixed response in other reports

Rituximab (chimeric anti-CD20

monoclonal antibody)

• In two phase-III trials found effective• Dose of 10 mg/kg/day on days 1, 14 and

28. and then it is given every 4 weeks.• [Annals of the Rheumatic Diseases 2012;71(11):1833–

8.].

Belimumab(B lymphocyte stimulator-specific

inhibitor)

By the III infusion : Lesions cleared completely without any post inflammatory pigmentation [Figure ‑2]. No further lesions or recurrence have been observed after one year of follow up.‑

Ustekinumab :45 mg dose SC at 0, 4, 16 and 34 weeks

SCLE

79 yr old lady with CCLE and DLE, refractory to topical and systemic glucocorticoids, hydroxychloroquine, azathioprine, thalidomide, methotrexate, topical calcineurin inhibitors, high-dose intravenous immunoglobulin.

Chilblain CLEActa Derm Venereol. 2012:doi:

10.2340/00015555-1467

• 28 yr old lady, SLE with TEN ( involving 70% BSA)• Refractory to iv methylprednisolone. • Plasmapheresis twice every week for 5 weeks.

Lupus 2008;17:605-6

IV Immunoglobulin• IVIg : costly

• SCLE showed greater degree of response than DLE

• Remission is short lived , relapses are common, so reserved for

severe refractory disease when long term therapies are initiated.

• Dose 1g/Kg IVIg for cosecutive days f/b 400mg/kg/month for 6

months

• CR or good response has been reported in a total of 21 patients with

CLE from six case reports (J Dermatolog Treat. 2004;15:46–50. Acta Derm Venereol.

2005;85:545–547. Clin Rheumatol. 2007;26:981–983. Clin Rev Allergy Immunol. 2010;38:307–318.)

Other investigational therapies• CYC : Toxic so for CLE not recommended• CsA : ACLE, LE non-specific cutaneous lesions (Rev Med• Interne 2008;29(9):701–9.)

• Methyl aminolevulinic acid photodynamic therapy (MAL-PDT)

• Oral Apremilast (a phosphodiesterase 4 inhibitor) [J drug dermatol 2012 ;11:1224]

• IV sirukumab (a human anti-IL-6 monoclonal antibody)

• Therapeutic modulation of class I interferon signalling : Upregulated

locally in cutaneous disorders including lupus-specific skin disease

• SC Efalizumab (anti-CD11a monoclonal antibody) : Ameliorate DLE and

SCLE. However, it has also been implicated in the induction of SCLE. (J Am

Acad Dermatol 2010;25),(Dermatol Clin 2010;28(3):489–99.)

Patient Education: Sun Protection

Widespread/scarring/severeLocalized Disease

Topical CS +/- CI+ HCQ Maintainin

Add quinacrine

Change HCQ to CQ & continue quinacrine

RTX, Belimumab, Plasmapheresis

Topical CS+/- CI

Maintain

PR GR

PR

Good respon

se

MTX

MMFDapsoneRetinoids

Thalidomide & IVIgShort term remission inducing agent

GRPR

PR

PR

Summary (contd)

• There is paucity of :

• Well-powered , adequately sized studies

• So more RCDBT are needed to assess the efficacy and safety of

alternate therapies.

• Q. Refractory lupus should be labelled only after there is :

• 1. No response to strict photoprotection• 2. No response to AM & CS• 3. Non-Lupus lesions have been excluded• 4. Adequate HCQ levels have been attained• 5. All of the above

Thanks a lot