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SYSTEMIC LUPUS ERYTHEMATOSUS
Q. What is SLE ? Ans: It is a multisystem disease characterized by the association of immunological abnormalities with pathological changes affecting multiple organ systems particularly the skin, joints and vasculature. Q. What is the age of onset? Ans It tends to occur in EARLY ADULT LIFE. Peak age of onset is 38 years in female and 44.2 years in males Q. What is the female:male ratio ? Ans: 8:1. Q. Any familial cases? Ans: yes, in 10%. Q. Discuss the ETIOPATHOGENESIS of SLE ? Ans: there are 4 theoretical sequential phases in the clinical expression of this disease---

(A) INHERITANCE OF SUSCEPTIBILITY GENE (B) INDUCTION OF AUTOIMMUNITY (C) EXPANSION OF AUTOIMMUNE PROCESS (D) IMMUNOLOGIC INJURY.
(A) SUSCEPTIBILITY PHASE: It involves the inheritance of genes that confer predisposition to SLE. There is a tenfold difference in the heritability of SLE between dizygotic and monozygotic twins suggesting the presence of at least 4 genes:  MHC class II DR gene.  Genes encoding complement proteins and TNF.  Genes mediating apoptosis  Genes involved in cell signaling process.  Genes for clearance of immune complexes. (B) INDUCTION PHASE: It is C/B the appearance of autoreactive T cells that exhibit the loss of self-tolerence. Mechanisms involved are  Failure of central thymic or peripheral tolerance mechanism.  Aberrant expression of HLA-DR molecule  Molecular mimicry induced by infection  Presentation of cryptic peptides during apoptosis. (C) EXPANSION OF AUTOIMMUNE PROCESS: During this phase, autoantibodies are produced by population of clonally expanded B cells which are directed against a limited number of nuclear and cytoplasmic antigens. 3 major targets are ----- Nucleosome ( anti-DNA & anti-histone)  Spliceosome ( anti-Sm & anti –RNP antibodies)  Ro and La molecules (anti-Ro and anti-La). These autoantigens are clustered in distinct structures at the surface of apoptotic cells. Once the immune tolerance to the intact particles is broken down, the autoantibody response diversifies to include more and more components of the complex. This phenomenon is called EPITOPE SPREADING. (E) IMMUNOLOGIC INJURY: The auto antibodies cause tissue injury by the following means :  Direct cell death  Opsonisation  Blocking of target molecule function  ADCC

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 IMMUNE COMPLEX DEPOSITION AND COMPLEMENT MEDIATED LYSIS. Q. Discuss the predispositions of SLE? Ans: (1) Role of genetics : evidences are as follows --- SLE is associated with HLA DR2 & DR3.  SCLE is associated with HLA B8, DR3.  DLE is associated with HLA B7, B8, DR2, DR3, DQA0102.  Genetic deficiencies of complement components including C2,C3,C4,C5 & C1 esterase inhibitor ------- are associated with DLE & SCLE.  TNF-α gene polymorphisms are implicated ---- this promotes TNF-α production ---- photosensitivity. (2) Role of UVL: it is the most important environmental factor in the induction of LE (UVB> UVA). Mechanisms involved are :  It injures keratinocytes ----- autoantigen release.( antigens expressed on the surface)  It alters cellular DNA ---- immunogenic  Causes the exaggerated release of immune mediators such as ---- IL-2, TNF-a, PGE, proteases, free radicals, histamine.  Induces the expression of adhesion molecule--- ICAM 1 --- increased vascular permeability and exudation of inflammatory cells.  UVL suppresses cutaneous T cells and Langerhans cells which suppress abnormal patterns of cutaneous inflammation. (3) Role of tobacco: presence of LUPOGENIC AROMATIC AMINO AMINES (4) Role of drugs: Induces T cell DNA hypomethylation ---- biological autoreactivity of lymphocytes. SKIN IS OFTEN SPARED IN DRUG INDUCED SLE. (5) Role of viruses :  Induce virus induced apoptosis ---- expression of sequestered antigens on the cell surface.  EBV causes the overexpression of bcl-2 in the viral infected B cells ---- uncontrolled growth of B cells. (6) role of endocrine factors: evidences are :  more in women  premenstrual flares  Precipitation of disease with OCP. (7) heavy metals : CADMIUN, GOLD AND MERCURY are associated with autoimmunity (8) silicon breast implant : associated with -- scleroderma  lupus like syndrome  fibrositis  inflammatory myopathy  autoimmune thyroid disease (9) diet : hemolytic anemia and high titers of ANA and anti – ds DNA antibodies are reported following ingestion of sprouts, alphalpha which contains the amino acid ------ L- canavanine. Q. Discuss the ARA criteria for the diagnosis of SLE Ans: There are 11 criteria of which 4 must be there to make a diagnosis. SENSITIVITY AND SPECIFICITY IS 96% criteria 1. MALAR RASH ( 50%) 2. DISCIOD RASH (25%) 3. PHOTOSENSITIVE 4. Oral ulcer (25%) defination It is a fixed erythema, flat or raised over the malar area tending to spare the nasolabial folds. Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions. Skin rash as a result of unusual reaction to sunlight by patient history or physician observation. Usually painless, observed by a physician.

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5. Arthritis (90%) Nonerosive arthritis involving 2 or more peripheral joints C/B  tenderness  swelling  effusion

6. serositis

a. pleuritis :
 pleritic pain complained by patient  rub heard by physician  pleural effusion in X-ray or clinical finding

b. pericarditis:
 rub heard by the physician  evidence of effusion  ECG. 7. RENAL DISORDER (67%) a. persistant proteinuria > 0.5 gm/day or, > 3+ if quantification is performed. b. cellular cast – red cell, hemoglobin, granular, tubular or mixed. 8. Neurologic disorder (25%). a. Seizures in the absence of DRUGS OR METABOLIC DERANGEMENTS. b. Psychosis in the absence of DRUGS OR METABOLIC DERANGEMENTS. a. HEMOLYTIC ANEMIA with reticulocytosis b. LEUCOPENIA < 4000 / microlitre on two or more occasions c. LYMPHOPENIA < 1500 / microlitre on two or more occasions d. THROMBOCYTOPENIA < 100000 / microlitre in the absence of offending drugs. a. anti-ds DNA b. anti- Sm c. antiphospholipid antibody based on the finding of -- Abnormal serum level of IgG or IgM anticardiolipin antibody.  Positive test for lupus anticoagulant ( see below)  BFPT for syphilis present for > 6 months and confirmed by TPI or FTA- ABS. An abnormal titer of ANA by IF at any point of time and in the absence of drugs known to be associated with drug induced lupus syndrome.

9. Hematologic disorder

10. immunologic disorder

11. ANA

Q. What are the immunological abnormalities of SLE? Ans: 1. Positive LE CELL TEST. 2. ANA 3. Anti cytoplasmic antibodies 4. anti- neuronal , anti-phospholipid, anti-platelet and anti-RBC 5. BFPT for syphilis.

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Q. What is LE cell ? Ans: LE cell is a PMN leukocyte (neutrophil or macrophage) which has ingested basophilic staining nuclear material from a degenerative white cell in presence of LE cell factor (anti – DNA Ab). Polymorphs containing homogenous pink purple inclusion showing no residual chromatin pattern can be accepted as LE cell. Nucleus (purple) of the polymorph is pushed to the periphery with a thin rim of cytoplasm (sky blue). Sometimes large masses of nuclear material are found extracellularly and these are surrounded by leucocytes forming ROSETTES. LE cell is present in 80% cases of SLE. If LE cells are present in large numbers, it suggests SLE. Occasional LE cell in ------ Chronic DLE  Drug induced LE  Systemic sclerosis  Rheumatoid arthritis. Q. What is the mechanism of LE cell formation? Ans: circulating ANA cannot penetrate intact cells. If cell nuclei are exposed, the ANA can bind to them ---- this denatures the nuclei( nuclei loses its chromatin pattern and becomes homogenous) and subsequent fixation of complement renders the antibody coated nuclei strongly chemotactic for the phagocytic cells. Q. What is LE cell phenomenon? Ans. It is the demonstration of LE cell in normal blood when a serum of a patient with LE cell factor has been added to it. Q. Is ANA specific for SLE? Why? Ans: No. ANA are not specific but are sensitive. Using human cells e.g. Hep2 cells as substrate, of ANA are positive in 95% cases SLE. ANA also occur in: Normal individuals (5-15% of normal individuals have low titres of ANA). Other autoimmune diseases. Chronic inflammatory conditions. Drugs  Viral infections. ANAs are directed against several nuclear antigens and can be grouped into 4 catagories : 1. Antibodies to DNA 2. Antibodies to histones. 3. Antibodies to nonhistone proteins bound to RNA 4. Antibodies to nucleolar antigens.     Clinically the most commonly used method to detect ANA is INDIRECT IMMUNOFLOURESCENCE. THE PATTERN OF NUCLEAR FLOURESCENCE SUGGESTS THE TYPE OF ANTIBODY PRESENT IN THE PATEINTS SERUM. 4 BASIC PATTERNS ARE RECOGNISED ------ HOMOGENOUS or diffuse nuclear staining: Reflects antibodies to CHROMATIN, HISTONES and occasionally DOUBLE STRANDED DNA.  RIM or peripheral pattern: Reflects antibodies to double stranded DNA. Specific for SLE.  SPECKLED PATTERN refers to the presence of uniform or variable sized speckles. It reflects the presence of antibodies to non-DNA nuclear constituents. These components are easily extractable with buffered salt solution and hence they are called EXTRACTABLE NUCLEAR ANTIGEN. Examples of ENAs are Sm antigen, RNP, and SS-A and SS-B reactive antigens. THIS IS ONE OF THE MOST COMMONLY OBSERVED PATTERNS OF FLOURESCENCE AND THEREFORE THE LEAST SPECIFIC.  Anti-Sm, Anti- U1RNP, Anti- SS-A, Anti- SS-B, Anti- topoisomerase 1 (Scl-70) ----- fine speckled.  Anti-centromere: CREST syndrome.  NUCLEOLAR PATTERN: refers to the presence of few discrete spots of fluorescence within the nucleus and represents antibodies to nucleolar RNA. Anti- U3RNP, Anti- PmScl, Anti- RNA polymerase. THE SO CALLED “SHRUNKEN PERIPHERAL PATTERN” IS THOUGHT TO BE ASSOCIATED WITH POOR PROGNOSIS AND HIGH INCIDENCE OF RENAL DISEASE.

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A titer of <1:16 ANA can be ignored. A TITRE OF 1: 64 IS SIGNIFICANT. Q. How many patients are ANA negative and how do they present? Ans: 5-10 % patients are ANA negative but anti cytoplasmic antibodies positive i.e. 60% have anti- Ro 30% have anti-La 25% have anti- ss DNA. THEY HAVE MANY SIMILARITIES LIKE SCLE like they have prominent malar rash, oral ulcers, photosensitivity and SCLE like skin lesions. Systemic manifestations of SLE are rare. Q. What are the markers of disease activity? Ans: 1. High serum levels of ANA 2. Anti- ds DNA 3. Low levels of serum complement. 4. DNA binding activity: Radiolabelled DNA is incubated in test serum and DNA- antiDNA complex are precipitated by 50% ammonium sulphate. Next the radioactivity of the supernatant and precipitate is compared. >30% is considered abnormal. HIGH BINDING IS ASSOCIATED WITH POOR PROGNOSIS AND RENAL DISORDER. Q. What are the biologically false positive tests for syphilis? Ans: Biologically false positive test are encountered in the standard nonspecific tests for syphilis where cardiolipin (purified extract of beef heart) is used as antigen and the antibodies are detected in the serum of patients. These tests include: 1. WASSERMANN CFT 2. KAHN TEST 3. VDRL SLIDE FLOCCULATION TEST 4. RAPID PLASMA REAGIN TEST 5. Automated RPR 6. VDRL- ELISA test. Conditions where we get these tests false positive: (A) ACUTE FALSE POSITIVE REACTION ( < 6 months)  Recent viral infection or immunisation  Genital herpes  Malaria  HIV infection  Parenteral drug use. (B) CHRONIC FALSE POSITIVE REACTION ( > 6 months)  Aging  SLE  AI disorders  RA  Parenteral drug use. Q. Discuss the significance of different autoantibodies in SLE? Ans:  Anti- ds DNA ( 70%): SPECIFIC FOR SLE . High titres associated with renal lupus and clinical activity.

 Anti- Sm (30%): SPECIFIC FOR SLE. Sm is a protein complexed to species of small nuclear RNA.
A/W renal, CNS disease and vasculitis.

 Anti – RNP (40%): characteristic of MCTD. It is a protein complexed to U1RNA.  Anti- Ro (30%): It is a protein complexed to y1-y5 RNA. A/W increased photosensitivity, renal disease,
neonatal LE, Sjogren’s syndrome, SCLE.

 Anti- histone (70%): Low incidence of renal and CNS disease. IT IS PRESENT IN 95% CASES OF DRUG
INDUCED SLE.

6  Anti – ribosomal P (20%): A/W CNS lupus. The antigen is ribosomal P protein.  Antineuronal antibody (60%): A/W diffuse CNS lupus. The antigen is present in the neuronal
surface.

 Anti – phospholipids antibody (50%): Thrombosis, Thrombocytopenia and Recurrent fetal loss.
 Other antibodies are anti-erythrocyte, anti- platelet, anti lymphocyte. Q. What is antiphospholipid antibody ? Ans: This is a antibody directed against PLASMA PROTEINS ( prothrombin, annexin V, beta 2 glycoprotein, protein C and Protein S) COMPLEXED WITH PHOSPHOLIPIDS . The antibody is an acquired immunoglobulin (IgG/IgM). Since phospholipids are needed for normal clotting process, these antibodies interfere with the normal clotting process. Hence they are also called as LUPUS ANTICOAGULANT. It is identified in vitro clotting tests like prolonged APTT and kaolin clotting time which is not corrected by normal plasma . Also by Russel Viper venom test. IT IS PRESENT IN 14% CASES OF SLE. It is also found in other conditions like---- Drug induced SLE  Other CTD  Carcinoma and lymphoma Despite the circulating anticoagulant, half of the cases with antiphospholipid antibody have a procoagulant effect. The possible mechanisms for this are:  Decreased prostacyclin release  Inhibition the anticoagulant effect of prostacyclin  LE anticoagulant + phospholipid fraction of platelets ---- activation of platelets ----- THROMBOSIS.  Direct endothelial injury. Q. What is antiphospholipid syndrome ? Ans: It is characterized by:  THROMBOTIC EPISODES in  legs ---- leg ulcer, gangrene, cutaneous necrosis  renal  cerebral  pulmonary  hepatic  Placenta ---- fetal death ---- recur in subsequent pregnancies.  LIBMAN SACKS ENDOCARDITIS  THROMBOPHLEBITIS  THROMBOCYTOPENIA ------- PURPURA, ECCHYMOSES.  BFPT for syphilis. All women with SLE, THROMBOSIS, and RECURRENT ABORTIONS AND BFPT for syphilis should be screened for LUPUS ANTICOAGULANT. Treatment with Prednisolone 40-80 mg daily with Aspirin 75mg daily ------RESULTS IN SUCCESSFUL PREGNANCY. Q. What are the poor prognostic factors in SLE ? 50% mortality in 10 years. Ans: (A) Serious renal involvement in the form of  High serum creatinine ( > 1.4 mg/dl)  Nephrotic syndrome ( 24 hr urinary protein > 2.6 gm)  Hypertension (B) Serious CNS involvement (C) Anemia. Thrombocytopenia (D) Hypocomplementemia suggesting hightened disease activity

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(E) Antiphospholipid syndrome (F) Low socio economic status Leading causes of death in the 1st decade = INFECTION and RENAL FAILURE. Leading causes of death in the 2nd decade = THROMBOEMBOLIC EVENTS. Q. Discuss the features of DRUG INDUCED SLE ? Ans.  Uncommon in blacks ( SLE is most common in American blacks)  Occurs in older age group (SLE occurs in the 2nd and 3rd decade mostly).  F:M = 4:1 (SLE = 8:1)  Increased incidence of HLA-DR4.  Occurs more in slow acetylators.  Renal and CNS involvement is uncommon. Most common systemic complaints are arthralgia.  Anti-histone antibodies are frequent – 95% (in SLE = 70%)  Anti DNA antibodies are absent  Serum complements are normal.  Typical skin manifestations of SLE are rare. They are mostly VASCULITIC, PYODERMA GANGRENOSUM like, BULLOUS, ERYTHEMA MULTIFORME like.  Resolves within weeks of stopping the drug. Others need a short course of steroids (2-10 weeks).  Symptoms rarely persist beyond 6 months. Q. What drugs are implicated in drug induced lupus? Ans.  Hydralazine  Procainamide  INH  Penicillamine  Griseofulvin  OCP  Beta blockers  Captopril  Gold  Minoxidil  Streptomycin  Penicillin  Tetracycline  Sulfonamides  Anticonvulsants  Chlorpromazine  Ibuprofen Q. Discuss the relation of pregnancy with SLE Ans. FERTILITY IS NORMAL IF RENAL FUNCTION IS GOOD. It is ideal for a girl to contemplate pregnancy when there HAS BEEN CLINICAL REMISSION FOR 6 MONTHS. This should indicate an uncomplicated pregnancy and live birth. Inactive disease is not associated with a disease recurrence. WORSENING OF SLE IS UNCOMMON IN PREGNANCY ESPECIALLY IN THOSE ON IMMUNOSUPPRESIVE THERAPY. IN PREGNANCY, IF THERE ARE  NO FLARES

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 NO NEPHROPATHY  NO PSYCHOSIS Then, safely continue pregnancy, otherwise institute steroids to prevent postpartum flares just before delivery. In less than 10% cases permanent detoriaration of renal function can occur. IN ALL PATIENTS , THERE IS A HIGHER RISK OF This may be because of immune complex deposition on the trophoblast basement membrane or the transplacental passage of antiphospholipid Antibodies ( anticardiolipin antibodies especially of IgG type or the lupus anticoagulant. In a case with recurrent abortions, it is ideal to screen for antiphospholipid antibody. If positive they should be treated with daily prednisolone and aspirin. HOWEVER, THE PRESENCE OF THESE ANTIBODIES WITHOUT RECURRENT ABORTIONS IS A NOT AN INDICATION FOR TREATMENT. A patient of SLE on low dose steroids can be maintained thus during pregnancy also (sometimes, high dose steroid during early pregnancy can cause cleft palate). Steroids can assist in the growth and pulmonary maturity of a child. THE DOSE OF STEROIDS HAS TO BE INCREASED DURING DELIVERY AND POSTPARTUM (STRESS). Also therapeutic abortion and caesarian section is contraindicated because of increased stress. For contraception, estrogen containing contraceptives are contraindicated. BARRIER CONTRACEPTIVES ARE INDICATED. Breast feeding is probably safe if the patient is on aspirin or low dose steroid but should probably be avoided if other immunosuppressives are used. Q. Compare SLE of childhood vs. elderly Ans.     : CHILDHOOD  Earliest age of onset is 3 months  The clinical picture, course and treatment are similar to the disorder in the adults but CHILDREN USUALLY HAVE A MORE SEVERE DISEASE.  Liver and lymph nodes are most commonly enlarged.  CNS & KIDNEY may be involved. ELDERLY  Increased incidence of lung disease and Sjogren’s syndrome and lower incidence of CNS disease and mesenteric vasculitis.  Anti-Ro and Anti- La are frequent.  Association with HLA – DR3. Premature delivery Fetal loss Perinatal mortality Abortion.

Q. What is NEONATAL LUPUS ERYTHEMATOSUS? Ans. It is a disorder thought to be caused by the transplacental passage of maternal antibodies. The most frequent manifestations are (A) CUTANEOUS LESIONS & (B) CONGENITAL HEART BLOCK. It might be related to HLA-DR3 haplotype. The antibodies mostly implicated are  Ro/SS-A antibody (100% cases of NLE): ANTI-Ro Ab is the MARKER FOR THE CONDITION . Used for prenatal diagnosis.  La/SS-B antibody( 50% cases of NLE)  U1RNP. These antibodies are not specific for NLE but are also seen in  Sjogren’s syndrome  SCLE  Normal population (0.5-2%). Approximately half of NLE patients manifest skin lesions which may be present at birth or occur in the first few weeks of life. The most common finding is an ERYTHEMATOUS SLIGHTLY SCALY ERUPTION ON THE FACE AND PERIORBITAL SKIN (raccoon sign/ owl-eye/ eye-mask) with the SCALP, TRUNK, EXTREMITIES, NECK AND INTERTRIGINOUS AREAS involved in the decreasing order of frequency. The eruption can be exacerbated by UV exposure and PHOTOTHERAPY. The rash improves by 4-6 months of life and has usually completely resolved without scarring BY 12 MONTHS.

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COMPLETE HEART BLOCK occurs due to fibrosis of the conducting tissue of the heart. There may be associated pericardial and pleural effusion, ascitis, cardiomyopathy, and IUGR and hydrops fetalis. Other features are --- Hepatosplenomegaly  Thrombocytopenia  Coomb’s positive hemolytic anemia  Neutropenia  Aplastic anemia  SPECKLED ANA AND ANTI-Ro ARE ALMOST ALWAYS PRESENT.  ARA criteria are not fulfilled  Involvement of joints, kidneys and CNS are rare. Treatment: 1. sun avoidance 2. topical steroid 3. pacing Regarding future pregnancies ---- ladies with anti-Ro/anti-La antibodies should be made aware of the possible problems.  The risk is low if such a lady does not suffer of CTD (SLE/ Sjogren) or gives birth to a child with NLE.  THE RISK RISES WITH  The presence of NLE in a previous child ( 25-50% risk)  PRESENCE OF MATERNAL LUPUS ( 1:60 risk)  PRESENCE OF HLA-DR3 in mother Prognosis : some children can develop SLE in later life and some mothers can develop CTD in later life. Q. what is the GILLIAM CLASSIFICATION OF SKIN LESIONS ASSOCIATED WITH LUPUS ERYTHEMATOSUS? Ans. Skin lesions are classified as 1. LE specific 2. LE non specific skin lesions. (1) LE specific skin lesions (A) ACUTE CUTANEOUS LE ( ACLE) : 80% of SLE cases have these and 20% present with these.  Localised ACLE ( malar rash) : butterfly blush or discrete maculopapular eruption with fine scaling on the “butterfly” distribution of the face.  Generalised ACLE (B) SUBACUTE CUTANEOUS LE ( SCLE)  Annular LE  Papulosquamous SCLE (C ) CHRONIC CUTANEOUS LE ( CCLE) : DLE lesions occur in SLE patients. In 10% they are the presenting lesion and in 33% they occur during the course of the disease.  Classic discoid LE  Hypertrophic / verrucous LE  LUPUS PROFUNDUS  Mucosal LE  Lupus tumidus  Chilblain LE  Lichenoid DLE  Bullous DLE  Rosacea like DLE  Annular atrophic DLE  LE gyratum repens  Rowell’s syndrome

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(2) LE nonspecific skin lesions (A) Cutaneous vascular diseases (a) VASCULITIS ---- LEUCOCYTOCLASTIC (palpable purpura, urticarial vasculitis) ---- PERIARTERITIS NODOSA. (b) VASCULOPATHY ----- Degos disease like lesions ----- Secondary atrophie blanche (c ) PERIUNGUAL TELANGIECTASIA (d) LIVEDO RETICULARIS---- COMMON IN PATIENTS WITH CNS LUPUS. (e) THROMBOPHLEBITIS (f) RAYNAUD’S DISEASE (g) ERYTHROMELALGIA (h) PURPURA ---- causes are : thrombocytopenia, cutaneous arteritis, steroid therapy. (B) Non scarring alopecia : mostly in active stage ( 50% of patients with active stage have this). Hair recovers once the disease becomes inactive but the lupus hair tends to persist longer.  Lupus hair: occurs in 30% patients. These are coarse, dry, brittle, broken off shortened unruly hair especially on the frontal margin. They have slowed anagen growth. They usually persist longer.  Telogen effluvium  Alopecia areata. (C ) Sclerodactyly, digital pitted scar (D ) Sclerodermatous skin changes in face and limbs although mat like telangiectasia are rare. (F) Panniculitis (G) Urticaria (H) Bullous lesion (I) Rheumatoid nodule (J) Papulonodular mucinosis (K) Calcinosis cutis (L) Erythema multiforme (M) Leg ulcer (N) Widespread icthyosis (O) Occlusion of large and medium sized arteries also occur suddenly---- may need amputation of the limb. Q. What are the changes of SLE in hand ? (A) Reticulate telangiectatic erythema on the palms ( thenar and hypothenar eminence), pulp and back of the fngers. (B) Small vascular necrosis on the tips of fingers and alongside the nails. (C) Ragged cuticle (D) Digital tip gangrene (E) Dilated nail fold capillaries (F) Over nails ---- splinter hemorrhages, pitting, ridging, onycholysis, striate leukonychia, clubbing (G) Recurrent osler’s nodes ---- painful erythematous papules on the pulp of the finger due to arteritis or embolism. Q. What are the vesicobullous skin changes in LE ? Ans. (A) LE specific  TEN like ACLE.

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 TEN LIKE SCLE.  Vescicobullous SCLE.  Bullous DLE. (B) LE      non specific Bullous SLE Bullous pemphigoid Dermatitis herpetiformis Pemphigus erythematosus Porphyria cutanea tarda.

Q. What is BULLOUS SLE ? Ans. It is a separate subset of SLE with subepidermal blisters and neutrophilic microabscess, nuclear dust and fibrin at the tips of the dermal papillae (like DH). It is a transient autoimmune blistering condition that occurs in the setting of SLE. IMMUNOFLOURESCENCE shows the linear deposition of IgA, G, M , C3 at DEJ ( unlike DH but like BP). However electron microscopy shows that the reactants are in the sublamina densa and not in the lamina lucida as in BP. TARGET ANTIGEN IS TYPE VII collagen (in some). Bulla predominantly occur in the face, neck and upper trunk but maybe widespread. Heal with scar and milia formation. Also, photosensitivity +. Nephritis is common. Also hypocomplementemia and anti-ds DNA . HYDRALAZINE can precipitate this. Treatment of choice is Dapsone alone or in combination with steroid. In resistant cases, thalidomide is used. Q. What is SENEAR – USHER SYNDROME ? Ans. It is also known as PEMPHIGUS ERYTHEMATOSUS. Here patients have immunological features of 2 diseases--pemphigus foliaceous and lupus erythematosus namely--- Granular IgG and C3 in the DEJ.  Intercellular IgG and C3 in the epidermis.  Circulating ANA.  CIRCULATING ANTIBODY AGAINST DG1 (160kD). But anti- ds DNA and ENA are absent. Progression to SLE is rare. It is characterized by RED SCALY LESIONS IN A BUTTERFLY DISTRIBUTION SIMULATING LE or SEBORRHOEIC DERMATITIS. PHOTOSENSITIVITY IS PRESENT. Lesions elsewhere like pemphigus foliaceous. Condition can be brought about by PENICILLAMINE, PROPANOLOL, CAPTOPRIL. It can be associated with thymoma and myasthenia gravis. Q. discuss the mucous membrane lesions of SLE ? Ans.  These occur in 26%.  They usually occur in the PALATE ( 82%), BUCCAL MUCOSA AND GUMS in the active phase of the disease.  Lesions start as small reddish or purplish areas which break to shallow ulcers with dirty yellowish base and a red halo.  Histology and immunology is like the skin --- this differentiates it from LP.

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     LIPS : cracked, oedematous and crusted. Tongue infarction may occur --- A/W anticardiolipin antibodies. Ulceration of the mucous membrane of the nose may lead to bleeding and perforation. Erythema can occur in other mucosal surface like the vulva and perianal area. HYDRALAZINE CAUSES OROGENITAL ULCERATION.

Q. Discuss the joint involvement of SLE? Ans.  Occurs in 90%  Manifestations are :  Symmetric small joint arthralgia, arthritis ( arthralgia > arthritis, erosions are less common, deformity is less than RA). DIFFERENCE BETWEEN JOINT INVOLVEMENT OF SLE AND RA. FEATURES Deforming arthritis Sc nodules X-Ray erosions Kidney involvement LE cell test ANA R-factor SLE 25% 5% rare common 80% 90% 40% RA Common 25% Common Rare 15% 20% 80%

 Other musculoskeletal manifestations include --- myalgia, myositis, tendonitis, avascular necrosis of bones. Q. Discuss the pulmonary involvement in SLE? Ans.  Most common feature is TRANSIENT PLEURISY. In two third some effusion develops.  Pulmonary function tests may show diffusion abnormalities even when no changes may occur in the Xray.  Lupus pneumonitis occurs with fever, dyspnoea, and cough. X-Ray shows fleeting lung infiltrates. This responds to steroids (the most common cause of infiltrates in SLE is INFECTION). HIGH INCIDENCE OF anti-Ro in pneumonitis.  Later, interstitial pneumonitis and pulmonary hypertension may develop.  In X- Ray: BILATERAL ELEVATION OF DIAPHRAGM WITH LINEAR SHADOWS OVER THE LOWER LUNG ZONES is characteristic of SLE. Q. Discuss about the renal changes in SLE? Ans.  Renal involvement is present in 67%.  The involvement is significant in assessing prognosis.  Most patients have Ig deposits in the glomeruli but only one half have clinical nephritis defined by proteinuria.  Classification of lupus nephritis ( WHO) CLASS I: normal glomeruli by light microscopy, electron microscopy and immunoflorescence. CLASS II: mesangial glomerulonephritis : there is CLASS III : focal glomerulonephritis A: focal segmental GN. mild proteinuria but the patients maintain good renal function. B: focal proliferative GN. Characterized by proteinuria (occasionally nephritic syndrome) and hematuria. CLASS IV: diffuse GN. : there is proteinuria, hematuria, RBC cast, nephrotic syndrome,renal insufficiency and hypertension. IMMEDIATE TREATMENT SHOULD BE STARTED AT THIS STAGE OTHERWISE PROGRESS TO RENAL FAILURE.

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CLASS V: diffuse membranous GN: severe proteinuria and nephritic syndrome. CLASS VI: Advanced sclerosing GN: ESRD.  INDICATIONS      OF RENAL BIOPSY : Presence of any active urine sediment. Proteinuria > 500-1000 mg/day Creatinine > 1.1 mg/dl Prior to initiating cytotoxic agents Restaging, prognosis and adjustment of treatment.

 PATIENTS AT RISK OF SEVERE NEPHRITIS:  With persistently abnormal urianalysis  High titres of anti-ds DNA  Hypocomplementemia.  PROGNOSIS:  Without renal involvement 15 year survival is 84%  With renal involvement 15 year survival is 57%. Q. Discuss the IF pattern in LE? Ans. Immunoglobulins ( mainly IgG also IgM, IgA) together with complement (C1,C3) and properdin can be demonstrated in the DEJ by immunoflourescence. Single immunoglobulin deposition which are less prominent in DEJ and more striking around the blood vessel----- favours another diagnosis (systemic sclerosis, DM, MCTD, RA, Sjogren’s disease, pemphigoid, DH, Hypocomplementemic vasculitis, erythema multiforme, porphyria, GA, NLD, GVHD, amyloidosis, pyoderma gangrenosum, leprosy, PLC).  DEPOSITION IS MORE IN LESIONS MORE THAN 6 WEEKS, OVER SUN EXPOSED AREAS, UNTREATED LESION.  Staining may be HOMOGENOUS ( chronic lesion), THREADY ( active lesion) or STIPPLED pattern ( in uninvolved skin).  + in 80% in sunexposed involved skin in SLE AND DLE.  + in three- forth in sunexposed uninvolved skin of SLE  + in half in nonexposed uninvolved skin of SLE. Presence of IgG suggests poorer prognosis.  Both fibrin and properdin have been demonstrated in the lesion of SLE --- PROPERDIN DEPOSITION IN NORMAL SKIN CORRELATES WITH DISEASE ACTIVITY .  Deposits are also present in the blood vessels in skin lesions and uninvolved skin.  Epidermal nuclear deposits usually giving a speckled IgG pattern occurs in the basal cells of epidermis. In DLE, deposits do not occur in the uninvolved skin. C1q is present in the deposits only in 29% of cases in DLE (vs. 90% in SLE). These patients have greater risk of SLE. Q. What is Lupus like syndrome? Ans:  There is C2 deficiency  Decreased incidence and low titres of anti- ds DNA.  Infrequent occurrence of immunoglobulin and complement deposition in the skin  Frequent anti- Ro antibody.  Decreased renal disease. Q. What are evidences for and against that DLE AND SLE are the same entity? Ans. (i) evidences in favour :  the cutanoeus lesions in both clinicohistologically are the same

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 certain clinical features are present in both  Similar lab abnormalities are present in both though more common in SLE.  DLE patients occasionally go on to develop SLE  SLE patients develop DLE lesions  Conditions like LUPUS PANNICULITIS occur in both the two conditions. evidences against:  The risk of patients of DLE developing SLE is very small. Higher in disseminated DLE ( 22%) compared to localised DLE ( 1.2%).  This risk is not increased by various forms of stress, UVL, drugs chemicals etc.  DIF pattern is different.  Age and sex pattern is different  3 forbidden clones of lymphocytes synthesizing cellular autoantibodies develop in SLE BUT only one develop in DLE.

(ii)

Those patients ( HLA-B8 +) who convert from DLE to SLE and those with SLE who have discoid lesions must be genetically predisposed to both the conditions. CONCLUSION: PATIENTS OF DLE WITH HEMATOLOGICAL AND SEROLOGICAL ABNORMALITIES ARE NOT CASES OF SLE IN DISGUISE BUT ARE CASES OF DLE , A SAPERATE ENTITY FROM SLE WITH DIFFERENT GENETIC BACKGROUND. Q. Risk factors for the development of SLE in a patient with DLE? Ans. (i) Diffuse nonscarring alopecia (ii) Disseminated DLE (iii) Female with DLE before 40 years. (iv) HLA-B8 type (v) Generalised lymphadenopathy (vi) Periungual nail fold capillaries (vii) Raynaud’s phenomenon (viii) SCLE/ACLE skin lesions (ix) LE nonspecific skin lesions like vasculitis. (x) Anaemia, leucopenia, high ESR, persistently positive ANA, hypergammaglobulinemia, BFPT for syphilis, positive sunprotective nonlesional lupus band test. (xi) Elevated soluble IL2 receptors. Q. Define DLE ? Ans. It is a relatively benign condition of the skin most frequently involving the face and characterized by VARIOUS SIZED, USUALLY COIN SHAPED, ERYTHEMATOUS, WELL DEFINED SCALY PLAQUES WHICH TEND TO HEAL WITH ATROPHY, SCARRING AND PIGMENTATION. THE SCALES ARE ADHERENT AND PLUG THE FOLLICULAR ORIFICES. The histology is characteristic. There are hematological and serological changes in about half of the patients and these changes, with other evidence, suggest an autoimmune etiology. LOCALIZED DLE: The lesions are confined to the face above the chin. DISSEMUNATED DLE: Lesions occur below the chin also. Hematological and serological abnormalities are more frequently seen. More chance of developing SLE. Q. what is the sex incidence and age incidence of DLE? Ans. F: M = 2:1, age of onset = 4th decade. Q. any familial incidence ? Ans. Yes, 4 %. Q. Discuss the etiology of DLE. Ans. (1) Genetic: > Associated with HLA-B7, B8, Cw7, DR2, DR3 AND DQw1. (2) Environmental:

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> Sunlight, Extreme cold, Strong winds, Premenstrual period and Early pregnancy. (3) Drugs > PENNICILAMINE, GRISEOFULVIN, DAPSONE. (4) Viruses. Q. Discuss the histopathology of DLE? Compare it with SLE AND SCLE. Ans. STRATUM CORNEUM: there is hyperkeratosis with follicular plugging. EPITHELIUM:  Thinning and flattening of the stratum malphigii.  Hydropic degeneration of basal cells (liquefaction degeneration): most significant finding.  Dyskeratosis  Basilar keratinocytes show individual cell necrosis (apoptosis ) ---- present as round- ovoid , homogenous eosinophilic structures 10 micrometer called CIVATTE BODIES present in lower epidermis or in the papillary dermis. They are PAS + , diastase resistant and on DIF contain IgG,M, complement and fibrin.  Basilar keratinocytes acquire elongated contours like their superficial counterparts rather than retaining their normal columnar appearance ---- squamotisation.  The undulating rete ridge pattern is gone ad replaced by a linear array of squamotised keratinocytes. BASEMENT MENBRANE:  Thickening and tortousity in long standing cases.  PAS+, diastase resistant material is found not only in the DEJ but along the follicular dermal junctions as well. These findings correlate with immunoreactant deposits.  Capillary walls show thickening, homogenization and increase in PAS staining intensity. STROMA:  Predominantly lymphocytic infiltrate arranged along DEJ, around hair follicles and appendages (with hydropic degeneration of basal cells).  By impinging on the pilosebaceous units, infiltrate causes gradual atrophy and disappearance.  Also dermis shows----- EDEMA, RBC extravasation and MELANOPHAGES, INTERSTITIAL MUCIN DEPOSITION. SUMMARY: The salient features in the HPE of DLE is ( at least 2 must be present) (A) Liquefaction degeneration of basal cell layer. (B) Degenerative changes in the connective tissue characterized by hyalinization, edema and fibrinoid change most marked immediately below the epidermis. (C) A patchy dermal lymphocytic infiltrate with few plasma cells and histiocytes particularly around the appendages. SPECIAL HPE features IN THE VARIENTS OF DLE : (A) VERRUCOUS DLE :  PAPILLOMATOSIS  LARGE NUMBERS OF DYSKERATOTIC KERATINOCYTES. (B) TUMID DLE:  DERMAL FORM OF LE without surface or epithelial changes  SUPERFICIAL AND DEEP DERMAL INTERSTITIAL AND PERIVASCULAR LYMPHOCYTIC INFILTRATE ASSOCIATED WITH STROMAL MUCIN DEPOSITS. (C) LE PROFUNDUS:  SUBCUTANEOUS TISSUE MAYBE INVOLVED WITH OR WITHOUT INFLAMMATION IN THE DERMIS AND DEJ.  LOBULAR PANNICULITIS ---- fat necrosis is followed by fibrin deposition leads to hyalinization of adipose lobules.  Stromal mucin deposition in well eshtablished cases.  Vascular changes like endothelial prominence, thrombosis, calcification and perivascular fibrosis . SCLE: It differs from SCLE in that the changes are most intense in the DEJ. They consist of ---- Less prominent hyperkeratosis and inflammatory infiltrate than discoid lesions

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    Hydropic degeneration of basal cells sometimes severe enough to form clefts. Colloid bodies ( common) Dermal edema Focal RBC extravasation and dermal fibrinoid deposits (common).

SLE: LIKE SCLE. INFILTRATE MAY GO UPTO THE SUBCUTIS. Q. Discuss the clinical features of DLE. Ans Type of DLE Features 1. Classic DLE: The classical ‘tin tack sign’ is also found in pemphigus foliaceous. 2.warty LE 3.tumid LE Well defined coin shaped erythematous plaques covered by prominent adherent scales that extend into the orifices of dilated hair follicles. They expand with erythema and pigmentation in the periphery while in the centre there is atrophy, telangiectasia and hypopigmentation. Warty hyperkeratotic lesion with red raised edge. Tissues are SWOLLEN, BRAWNY, WARM AND TENSE. The surface shows reddish mottled appearance due to scarring. Many centimeter in diameter Centre Of the plaque is depressed and sclerotic resembling morphea Migratory gyrate annular erythema with HPE features of DLE. LUPUS BAND TEST NEGATIVE. There may be underlying carcinoma. Chilblains develop usually after some years of development of DLE lesions on the face. DLE usually remit but chilblain persists longer than cool months. Features Nodular lesions of various sizes, firm, rubbery, sharply demarcated and persistent. The overlying skin is normal. Healing with depressed areas or areas of anetoderma. Violaceous scaly tender lesion rapidly enlarges and develops into a hard, brown black tarlike plaque. Reddish nodular lesions on the nose, cheeks, forehead and sometimes the chin A/W diffuse redness and easy flushing. NO PUSTULES. The EM lesions last from a few days to over a month. There are no precipitating factors for EM. PATIENTS FREQUENTLY HAVE PERNIOTIC LESIONS ALSO.

Sites Face (check, bridge of the nose), scalp, ears, V areas of the neck, extensor aspect of the arm, forearm, hands, back and sides of the toes.

Mostly seen on the nose, temples, ears, scalp, palms and soles. May involve a whole cheek or limb. Face, neck, behind ears.

4.annular atrophic 5.LE gyratum repens 6.Chilblain lupus (6%). More in female

Chilblain over acral areas,ears, nose

Variant of DLE 7. LE profundus. An unusual variety of LE in which cut. Infiltrate occurs primarily in the deeper portions of corium with only microscopic epidermal changes. 8.LE hyperthrophicus et profundus 9. rosaceous LE: 7.5%

site Cheeks (most common), face, arms, breasts ( lupus mastitis, may herald SLE), buttocks, trunk or legs. 50% have SLE ( less severe than the typical SLE) Face, arms, dorsal aspect of hands and back. FACE

10. BULLOUS DLE 11. ROWELL ’S SYNDROME: ERYTHEMA MULTIFORME occurs in association with DLE/SLE. Speckled type of ANA is A/W Rheumatoid factor

Sites of EM are ---UPPER PART OF THE BODY including face

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and anti-La(SS-B)

12. MUCOSAL DLE: 25% of DLE patients have mucosal lesions. 13. NAIL DLE

14. LE telangiectoides: occurs in SLE & DLE.

Mostly affects the oral mucosa as LP like lesions,erythematous patches with depressed centre, superficial ulcerations, lip crusting, scar, leukoplakia and SCC. Lower palpebral conjunctivitis, superficial punctuate keratitis, Redness in the vulva and anus. Nail fold- erythema, telangiectasia, clubbing, paronychia Nails – red lunula, pitting, leukonychia striata, onycholysis, subungal hyperkeratosis. C/B persistent blotchy reticulate in the face, neck, ears, back telangiectasia . Healing by of hands, breasts, heels and punctuate atrophic scarring. sides of feet

Q. What are the associations of DLE? Ans.  Facial telangiectasia  Bilateral enlargement of parotid  Livedo reticularis  Porphyria  Pemphigus  Myasthenia, thymoma  Hereditary C2 deficiency. Q. what percentage of DLE patients have scalp involvement? Ans: Scarring alopecia develops in one third and usually permanent. Q. What are the lab abnormalities in DLE Ans. Frequency of lab abnormalities is less in DLE compared to SLE  HEMATOLOGICAL--- Anemia, leucopenia, thrombocytopenia ( one third)  Raised ESR (20%).  Positive Coomb’s test.  Cryoglobulins and cold agglutinins  Hypergammaglobulinemia  BFPT for syphilis --- 26%.  LE cell test --- 1.7%  ANA ---- 35%, HOMOGENOUS = TWICE SPECKLED.  Anti-ssDNA + in one fifth.--------- A/W WIDESPREAD AND PROGRESSIVE DISEASE.  Anti- dsDNA + in 0-27% cases. Q. Which cases of DLE take a long time to remit ? Ans.  Lesions of long standing with much scaling and scarring  H/O Raynaud’s phenomenon, chilblains  Scalp involvement. Q. What percentage of LE patients present with SCLE ? Ans. 10%. Q. What is the presentation of SCLE? Ans. There are mainly 2 types of lesions :  NONSCARRING PAPULOSQUAMOUS ( two third)  ANNULAR POLYCYCLIC ( one third) Lesions mainly occur above waist and particularly around the neck, on the trunk and outer aspects of the arms. The borders may show vesciculation and crusting. FOLLICLAR PLUGGING AND HYPERKERATOSIS are not

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prominent and the lesions resolve leaving grey white hypopigmentation and telangiectasias. The pigmentary changes eventually resolve spontaneously. Other features are ----Photosensitivity ( 50%) Diffuse nonscarring alopecia ( 50%) Mouth ulcers Livedo Periungual telangiectasia Localised scarring DLE.

     

Q. How many fulfill the ARA criteria? Ans. 50%. Arthritis is the most frequent systemic feature. Other systems involvement are rare. Q. ANA is positive in how many ? Ans. 60-80%. Homogenous variety. Q. anti-Ro and anti-La positive in how many ? Ans. 70-90% and 30-50%. Q. lesional lupus band test positive in how much ? Ans. 60%. Dust like particle pattern of IgG deposition around epidermal basal keratinocytes is more specific of SCLE. Reflects in vivo bound Ro/SS-A antibody. Q. HLA predisposition in SCLE ? Ans. HLA B8 and DR3. Q. What drugs precipitate SCLE ? Ans.  Griseofulvin  Terbinafine  ACE inhibitor  CCBs  Hydrochlorthiazide  Sulfonylureas. Q. discuss the treatment of LE. ANS. TREATMENT OF DLE 1. GENERAL MEASURES:  Sun protection  sunscreen 2. FOR RAYNAUD’S:  Pentoxyphylline  Other vasodilator ( CCBs) 3. TREATMENT PROPER : (A) TOPICAL : Topical/IL steroids; IL Interferon alpha; laser. (B) SYSTEMIC: --- ORAL ANTIMALARIAL: Hydroxychloroquin :400mg BD or 800mg BD for 6 months. After stopping treatment, 50% relapsed within 6 months and repeat courses are effective. However severity of relapses decreases with time. ---- SYSTEMIC GLUCOCORTECOID: daily pred 5mg OD/TDS OR, Pulse therapy ( Psoriasiform scalp lesions) --------------------BETA CAROTENE 50mg TDS CLOFAZIMINE 100 mg daily DAPSONE 100 mg daily ETRETINATE (1mg/kg/day): with chloroqiun was effective in WARTY VARIETY . ISOTRETINOIN ( 80mg/day)

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---- THALIDOMIDE: For cases not responding to antimalarials, topical steroids and sunscreen. 100-200 mg /day for 4-6 weeks then taper to 25-100 mg as maintenance. After stopping treatment, 71% relapsed but further courses were effective (C) MISCELLENEOUS : Cyclophoshamide ( 50-200mg daily) Azathioprin Large doses of vitamin E Sulfasalazine 0.5mg TDS. Phenytoin 100mg TDS. (D) SURGERICAL INTERVENTION ---- LASER ---- DERMABRASION ---- EXCISION. TREATMENT OF SLE 1. GENERAL MEASURES ---> Sun protection > Bed rest during exacerbation > Avoid secondary infection, mental and physical stress > Correct anemia 2. SPECIFIC TREATMENT IN SPECIAL CONDITIONS > for hypertension ---- hydralazine > diuretics for edema > anticonvulsants for epilepsy > NSAIDS for arthralgia 3. TREATMENT PROPER ---topical : steroids, tacrolimus systemic :  Corticosteroids : in acute cases start with 60mg daily---- taper gradually to a maintenance of 515 mg daily.  Antimalarials  Immunosuppresives :  Cyclophosphamide : 1.5 – 2.5 mg/kg daily. Indicated in very severe disease, organ or life threatening potentially reversible.  Azathioprine : in moderately severe disease with slow detoriaration alongwith high dose steroid  Methotrexate : 7.5 mg weekly in steroid resistant cases without renal and CNS involvement. 10-20 mg in mucocutaneous lesions.  Cyclosporin: 3-5 mg/kg used in resistant cases.  Methyprednisolone pulse: for patients not controlled by oral prednisolone and immunosuppresives.  Plasmapheresis: In patients with high levels of immune complexes whose condition is deteriorates despite other therapy. 3-4 days/week over a period of 2-3 weeks. Useful in managing life threatening complications like fulminating vasculitis or CNS disease.  IV gamma globulin  Dapsone: 200-300 mg daily.  Thalidomide  Retinoid  Interferon alpha, vitamin E, phenytoin, sulphasalazine, danazol, phototherapy

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