Connective Tissue Diseases Dr. Vinitha Varghese Panicker Associate Professor, Department of Dermatology, Amrita Institute of Medical Sciences & Research Centre, Cochin Digital Lecture Series : Chapter 19

CONTENTS  Lupus erythematosus (DLE / SCLE / SLE)  Scleroderma (Morphoea / Systemic Sclerosis)  Dermatomyositis / Polymyositis  Rheumatoid arthritis  Sjogren’s syndrome  Mixed connective tissue disease  Antiphospholipid antibody syndrome  MCQs  Photo Quiz

Lupus Erythematosus (LE)- Types Cutaneous lupus erythematosus is classified into three subtypes: Acute cutaneous lupus erythematosus (ACLE):  Malar rash, Morbilliform rash, bullous lesions Subacute cutaneous lupus erythematosus (SCLE):  Annular, Papulosquamous Chronic cutaneous lupus erythematosus (CCLE):  Discoid Lupus Erythematosus

Pathogenesis of Cutaneous LE  Genetic Factors - HLA susceptibilty  Environmental triggers - UV exposure induces cytokine release and apoptosis.  Immunologic factors - Malfunction of T regulatory cells (T reg) Role of IL-18

Localised ACLE -  Characteristic butterfly facial rash Generalised ACLE -  Widespread maculopapular rash in a photo-distributed pattern Acute Cutaneous LE

 Non - scarring; papulosquamous / annular polycyclic lesions.  Vesiculation, crusting, hypopigmentation, telangiectasia, alopecia, photosensitivity, Raynaud’s phenomenon.  Sites : above waist, neck, arms.  Systemic involvement 35%.  ANA, anti - Ro, anti - La. Subacute Cutaneous LE

 DLE is a relatively benign disorder of the skin, characterized by well defined, reddish, scaly patches which tend to heal with atrophy, scarring and pigmentary changes.  The histology is characteristic.  Female : Male - 2 : 1  Onset - second-fourth decade of life  Family history : 4%  Genetic factors - HLA B7, B8 Chronic: Discoid Lupus Erythematosus (DLE)

Discoid rash

 Histopathology : Epidermal atrophy, basal layer liquefaction, lymphocytic dermal infiltrate and ‘Civatte bodies’.  Differential diagnosis : Polymorphous Light eruption, Morphoea, Lichen planus, Lupus vulgaris, Sarcoidosis. Diagnosis

 Definition : A systemic disease with immunopathological abnormalities affecting various organs particularly the skin, joints and vasculature. Females > males Onset: early adult life Systemic LE

 Fever (52%), lymphadenopathy  Arthritis (84%) and arthralgia  Cutaneous lesions : specific and non -specific  Raynaud’s phenomenon  Renal - nephritis or as nephrotic syndrome.  Lung-pleural effusion, alveolitis, interstitial lung disease  Cardiac-pericardial effusion, myocardial infarction, Libman-sacks endocarditis Clinical features

 CNS involvement : migraine, epilepsy, neuropathy.  GIT and hepatic involvement : vasculitis of gut, ascites, pancreatitis, autoimmune hepatitis.  Splenomegaly, hepatitis, cirrhosis.  Hematologic-Anemia, leukopenia, Thrombocytopenia.  Ocular - Conjunctvitis, episcleritis, Retinal vasculitis.

 LE specific ACLE – Malar rash SCLE – Annular, Psoriasiform CCLE – Plaque Lupus panniculitis Hypertrophic Tumid CCLE Chilblain CCLE Mucosal CCLE Cutaneous lesions

Malar rashOral ulcer

 Vascular: Telangiectasia, Purpura, Thrombophlebitis, Raynauds phenomenon, livedo reticularis, erythema multiforme  Alopecia: Lupus hair, Alopecia Areata, Scarring Alopecia  Mucus membrane lesions  Nail changes  Calcinosis cutis  Bullous lesions  Urticaria  Pigmentary abnormalities  Sclerodactyly and sclerodermatous changes  Papulonodular mucinosis  Anetoderma  Lichen planus  Porphyria cutanea tarda LE Non specific lesions Contd…

 SLE in pregnancy  Neonatal LE  Drug induced LE  Childhood SLE  Rowell’s syndrome Special subsets of LE

 CBC : anemia, leukopenia, thrombocytopenia  ESR : raised  Urine analysis, BUN, S. Creatinine  False positive VDRL & RA factor  LE cell test  ANA  Anti-DNA, anti-Sm, anti-histone, cryoglobulins, serum complement levels  DIF – Lupus band test Investigations

ANA Patterns ANA PATTERNPREDOMINANT ANTIGENDISEASE PERIPHERALnDNASLE HOMOGENOUSnDNA, histonesSLE NUCLEOLARNucleolar RNASSc, SLE CENTROMEREKinetophoreCREST syndrome SPECKLEDVarious RNPs MCTD, SLE, SSc, Sjogrens syndrome

 Malar rash  Discoid rash  Photosensitivity  Oral ulcers  Non–erosive arthritis  Serositis : pleurisy or pericarditis  Renal disorder : persistent proteinuria (>0.5g/day) or cellular casts  Neurological disorders : seizures or psychosis American College of Rheumatology, ACR criteria Contd…

 Haematological disorders - heamolytic anemia or leukopenia (<4000/mm3) or lymphopenia (<1500/mm3) or thrombocytopenia (<1,00,000/mm3).  Immunological disorder - LE cells, or anti-dsDNA antibody or anti Sm antibody or false positive VDRL.  Antinuclear antibodies. 4 or more criteria are required for definitive diagnosis. American College of Rheumatology, ACR criteria

Clinical and Investigative criteria  Acute or subacute cutaneous lupus  Chronic cutaneous LE  Oral/nasal ulcers  Non Scarring Alopecia  Inflammatory synovitis  Serositis  Renal-Rbc casts, urine protein/creatinine atleast 500 mg protein/24 hr  Neurologic  Hemolytic anemia  Leukopenia (<4000/mm) atleast once or lymphopenia (<1000/mm) atleast once. SLICC CRITERIA (Systemic Lupus International Collaborating clinics) Contd…

 Thrombocytopenia  Immunologic criteria – ANA above reference range Antids DNA above lab ref range Anti-Sm Antiphospholipid antibody Low complement-C3,C4,CH50 Direct Coombs test in absence of hemolytic anemia Patient may be classified as having SLE if: patient has biopsy proven lupus nephritis with ANA or ds DNA antibodies or if they satisfy 4 criteria including at least one clinical/ one immunologic. SLICC CRITERIA (Systemic lupus International Collaborating clinics)

Mild disease  NSAIDs, topical therapy, antimalarials Severe disease  Systemic steroids  Steroid sparing immunosuppressants - Azathioprine, Cyclophosphamide, Mycophenolate mofetil  Biologics - Rituximab-monoclonal ab targeting CD20 receptor protein on surface of B cells-mainly for arthritis and proteinuria. Treatment

Definition :  Sclerosis confined to the skin, localised or generalized is termed as ‘Morphoea’.  Female : Male - 3 : 1  Onset : years;  Precipitating factors : Trauma, vaccination, radiotherapy, hormonal factors, borrelia infection, measles, silicone implants. Morphoea

 Plaque type - morphea en plaque, guttate morphea, keloid (nodular) morphea, atrophoderma of Pasini and Pierni.  Generalised morphea  Bullous morphea  Linear morphea - linear type, en coup de sabre, progressive hemifacial atrophy.  Deep Morphea - Subcutaneous morphea, eosinophilic fasciitis, morphea profundus, disabling pansclerotic morphea. Types of Morphea

Plaque type -  Round or oval indurated plaques with lilac border.  Heals slowly with residual hyperpigmentation.  Multiple, asymmetrical distribution.  Sites : trunk, limbs, face. Linear Morphea - Plaques of morphea in linear arrangement mainly on limbs Type on frontoparietal region - en coup de sabre Clinical features

En-Coup-de-Sabre

 Triamcinolone acetonide, mg/ml intralesional injection  Penicillamine : mgs / day  Diphenylhydantoin  Systemic steroids  Cyclosporine,  Topical Vit. D3 analogues  Topical tacrolimus  Phototherapy, plasmapheresis, physiotherapy, plastic surgery Treatment

 Systemic sclerosis is a multisystem autoimmune disorder characterized by vascular abnormalities, connective tissue sclerosis and atrophy.  Females : Males : 1  Onset : Fourth decade  Etiology and pathogenesis : complex autoimmune disease charecterised by immune activation, fibrosis of skin and obliterative vasculopathy. Systemic Sclerosis

 Limited Cutaneous Scleroderma - skin sclerosis of fingers (sclerodactyly) with or without mild sclerosis of face, neck and armpits.  Diffuse cutaneous Scleroderma - Diffuse and truncal sclerosis.  Immediate cutaneous scleroderma - Sclerosis of upper and lower limbs, neck and face without truncal involvement.  Sine scleroderma SSc - Absence of cutaneous sclerosis with typical visceral organ involvement, capillaroscopy changes and serum autoantibodies. Classification According to Skin sclerosis

 Raynaud’s phenomenon  ‘Hide-bound’ skin  Classical sclerodermoid facies- “mask-like” face, pinched or beak-like appearance of nose, radial furrows around the mouth and thinning of the upper lip  Pigmentation – mottled or hyperpigmentation  Swelling of hands & joints, atrophy  Finger and leg ulcers, digital gangrene, stellate scars  Nail fold telangiectasias  Calcinosis Cutaneous features

Pitted scars Features of syctemic sclerosis Classical sclerodermoid facies

 Gastrointestinal and Hepatic - Esophageal Dysfunction, malabsorption, primary biliary cirrhosis, Autoimmune hepatitis.  Arthritis, tendon friction rubs.  Renal-scleroderma renal crisis (most severe).  Lung-Interstitial lung disease, Pulmonary hyertension.  Cardiac-myocardial disease, pericardial involvement.  Muscle-SSc Associated myopathy more common in diffuse SSc. Systemic Features

2013 ACR/EULAR criteria -  Skin thickening of the fingers extending proximal to MCP jts is sufficient to diagnose the patient as SSc.  If this is not present seven other features apply with for varying weights for each - Skin thickening of fingers Finger tip lesions Telangiectasia Abnormal nail fold capillaries Interstitial lung disease or pulmonary artery hypertension Raynaud’s phenomenon Ssc related autoantibodies (anticentromere, antitopoisomerase, antiRnp-3) Diagnosis

 Serology - ANA, anticentromere antibodies, anti-Scl 70 antibody  Pulmonary Function test -Detect fibrotic changes  Histopathology - Hyalinization and homogenisation of collagen, dermal lymphocytic infiltrate.  ECG- To detect rhythm and conduction abnormalities.  ECHO- Detect pulmonary artery hypertension.  GI involvement- Esophageal manometry, endoscopy, barium studies. Investigations Contd…

 Use of gloves  For Raynauds - nifedepine (mild cases), sildenafil, iloprost, low molecular weight dextran.  Corticosteroids  Immunosuppressants : Methotrexate, Cyclophosphamide  Penicillamine, colchicine, interferons.  Symptomatic treatment for pulmonary, cardiac, renal and GIT symptoms. Treatment

 An idiopathic inflammatory myopathy characterised by muscle weakness and cutaneous eruption.  Females > males  Bimodal peak during childhood and then between yrs  ETIOLOGY  HLA-B8, DRB1*0301, DQA1*0501, DQA1 *0301  Infections - Gr A Beta hemolytic streptoccoci, toxoplasma, coxsackie  UV radiation exposure  Drugs-d penicillamine, tamoxifen, INH, penicillins Dermatomyositis

 Pathognomic skin manifestation - Gottrons papules and Gottron’s sign.  Gottrons papules - violaceous papules overlying the dorsal interphalangeal and metacarpophalangeal joints, elbows and knees.  Gottrons sign - erythematous or violcaeuos erythema with or without edema.  Characteristic skin lesions - heliotrope erythema and macular violaceous erythema over the deltoids, posterior shoulders, nape of neck, upper chest (V sign), forehead and dorsa of hands.  Cutaneous calcinosis more common in JDM, 40-75% cases. Cutaneous features

HeliotropeGottron’s papules

 Muscle : Progressive symmetric proximal myopathy; pharyngeal and respiratory muscles may be involved.  Joints : Non erosive arthritis, usually an early manifestation.  Pulmonary : Aspiration pneumonia, Interstitial lung disease, Hypoventilation.  Cardiac : Arrythmia, conduction abnormalities myocarditis.  Gastrointestinal : Dysphagia, esophageal reflux. Systemic manifestations

 Symmetric muscle weakness  Elevation of skeletal muscle enzymes  Abnormal EMG results  Muscle biopsy results  Typical rash of DM Definite diagnosis : characteristic skin rash + ¾ remaining criteria. Criteria for diagnosis (Bohan and Peter)

 Muscle enzymes : CK, SGOT, SGPT, LDH, S. Aldolase  CK - MM fraction most specific for skeletal muscle  Muscle biopsy - definitive diagnosis  EMG  MRI - may detect subclinical muscle involvement.  Serology : ANA, anti Jo - 1, anti - Mi 2 Investigations

 Corticosteroids  Immunosuppressants : Methotrexate, Mycophenolate mofetil Cyclophosphamide, Azathioprine  Methotrexate considered first choice among adjuvants  IV Ig - refractory cases  Rituximab  Exercise and physical therapy  Cutaneous lesions - Sunscreens, Hydroxychloroquine,  Calcinosis - alendronate, diltiazem, excision of large lesions Treatment

 Affects predominantly females  Features of SLE, systemic sclerosis, dermatomyositis, polymyositis  Specific antibody to U1-RNP.  Raynaud’s phenomenon, arthritis, arthralgia, sausage shaped fingers, swelling of hands, photosensitivity, SCLE like rash.  Abnormal oesophageal motility, impaired pulmonary diffusing capacity, myositis, aseptic meningitis, psychosis, trigeminal neuropathy. Mixed Connective Tissue Disease

 Xerostomia with keratoconjunctivitis sicca Cutaneous features :  Xerosis, Generalised pruritus, Loss of sweating, Diffuse alopecia, Recurrent annular erythema.  Raynaud’s phenomenon, Non thromobocytopenic Purpura, Urticarial vasculitis, necrotising vasculitis, splinter hemorrhages, gangrene. Sjogrens Syndrome

Specific manifestations :  Rheumatoid Nodules - most frequent extra-articular manifestation.  Granulomatous dermatitis - linear erythematous to violaceous subcutaneous bands in axilla, trunk, inner aspect of thighs.  Rheumatoid Vasculitis - Ulcers, digital infarcts, nail fold infarcts (Bywaters lesions)  Pyoderma gangrenosum  Feltys syndrome  Juvenile onset RA Non Specific Manifestations :  Palmar erythema, sclerodactyly like changes, periungual erythema, splinter hemorhages, bluish discoloration of fingers. Cutaneous Manifestations of Rheumatoid Arthritis

 Primary and Secondary  Secondary causes include - autoimmune connective tissue diseases, Takayasu’s arteritis, bacterial and viral infections, malignancies, dialysis in renal failure.  Approx 40% have cutaneous manifestations.  Livedo reticularis most common.  Others - necrotising vasculitis, thrombophlebitis, cutaneous ulcers, gangrene, necrosis, purpura, erythematous macules, ecchymoses, painful skin nodules, anetoderma, atrophie - blanche like lesions, subungual splinter hemorrhages. Antiphospholipid Antibody Syndrome

Q.1) Carpet tack sign is seen in A.SCLE B.DLE C.SLE D.Bullous LE Q.2) Rowells syndrome is A.Lupus panniculitis B.LE and EM like lesions C.LE and Scleroderma D.Neonatal LE MCQs

Q.3) Pathognomic skin lesion of Dermatomyositis A.Gottron’s papules B.Heliotrope erythema C.Shawl sign D.Poikiloderma vasculare Q.4) Water melon stomach is seen in A.SLE B.Systemic Sclerosis C.Dermatomyositis D.MCTD MCQs

Q.5) 53 year old lady presents to the medical assessment unit with a flu-like illness and myalgia. In the last few days she has noticed a rash across her back. She has no other symptoms. On examination she looks unwell. There is an erythematous rash across her back. She has grade 4/5 weakness proximally. Her CK which is elevated at 1052 IU/l. Her renal function is normal. What is the diagnosis? A.SLE B.Systemic Sclerosis C.Dermatomyositis D.Antiphospholipid antibody syndrome MCQs

Q. Identify the condition. Photo Quiz

Q. Identify the condition.

Photo Quiz

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