CLINICO-PATHOLOGICAL CONFERENCE BY Medical Unit 1 BBH

CLINICAL SCENERIO A PATIENT WITH COLD SENSITIVITY AND ORBITAL PUFFINESS PRESENTED BY DR AMBER FAYYAZ JAFRI PGT MU I,BBH

PERSONAL PROFILE Name : Alina Age: 23 yrs Gender : Female Marital status: Unmarried Occupation: Nil Residence: Rawalpindi DOA: 9th February 2016. MOA: OPD

Presenting Complaints Gen. body aches 6 months Multiple joint pains 2 months Fever 3 weeks Oral ulcers 3 weeks Periorbital puffiness 3 weeks Swelling of hands 3 weeks

HISTORY OF PRESENTING ILLNESS Generalized body aches 6 months Polyarthritis with morning stiffness two months. Low grade intermittent fever of three weeks . Periorbital puffiness associated with purplish discoloration of eyelids Oral ulcers Raynaud's phenomenon

SYSTEMIC INQUIRY Dysphagia Neuropsychiatric symptoms Hematuria Myalgias Important negatives Dysphagia Neuropsychiatric symptoms Hematuria Pleuritic chest pain Abdominal pain Skin tightness Dryness of skin and eyes

Family history:- Not significant Past medical and surgical history:- Personal history :- Non smoker, non addict. No known allergies. Menstrual history:- Normal.

General Physical Examination A young lady with following findings. Digital infarcts Multiple oral ulcers Heliotrope rash Few subcentimeter posterior cervical lymph nodes Swelling of hands and periorbital puffiness Vitals BP : 110/70 mmHg Pulse : 84/min Temp : 98.6 oF R/R : 20/min

Systemic Examination MUSCULOSKELETAL SYSTEM : There was no visible deformity of the joints Tenderness and swelling of small joints No limitation of movements

CARDIOVASCULAR SYSTEM RESPIRATORY SYSTEM Unremarkable CARDIOVASCULAR SYSTEM No signs of pulmonary hypertension

GASTROINTESTINAL SYSTEM Unremarkable CENTRAL NERVOUS SYSTEM:- Higher mental functions : intact Cranial nerves : intact Sensory and Motor examination: intact Cerebellar signs : Absent Gait : normal

DIFFERENTIAL DIAGNOSIS SLE RA Scleroderma Dermatomyositis Mixed connective tissue disorder Overlap syndrome Undifferentiated connective tissue disorder

INVESTIGATIONS

Blood CP TLC : 2.5 (Decreased) RBC : 4.05 Hb: 9.6 g/Dl (Decreased) MCV : 81.7 FL Platelet : 100 (Decreased) ESR : 98(Raised) CRP: 12 (Raised)

Biochemistry Urine R/E , LFT’S, RFT’S : Normal Serum LDH : Normal Coomb’s test : Negative.

ECG ECG: Normal. No feature of pulmonary arterial hypertension.

IMAGING Echocardiography :- Ultrasound abdomen : CXR: Normal No evidence of pericardial effusion or any valvular abnormality. Ejection fraction 55%. No evidence of hypokinetic walls.

Autoimmune profile RA :+ve Anti CCP antibodies : +ive

Autoimmune profile ANA : +ve Anti ds DNA : -ve Complement C 3 : 0.2 (0.7- 1.7)(Decreased) Complement C4 : 0.05 (0.2- 0.5)(Decreased)

Autoimmune profile Anti Smith antibody : -ve Anti SSA (Ro) : +ve Anti SSB (La) : +ve Anti Jo 1 antibody : -ve Anti scl 70 : +ve

Muscle enzymes Aldolase : Raised (19.5u/L) CPK : Raised (866mcg/L)

Autoimmune profile continued Anti U1 RNP Antibodies: -ve

Electromyography Excessive spontaneous activity. Polyphasic potential of short duration with low amplitude

DIAGNOSIS Based on the history ,examination, laboratory investigations and careful scrutiny of various features present in this patient suggestive of more than one autoimmune disorder .

SLE DIAGNOSTIC CRITERIA (2015 ACR) CLINICAL CRITERIA OUR PATIENT Malar rash _ Discoid rash Photosensitivity Oral ulcers + Arthritis Serositis - Renal involvement Neurological involvement Heamatological involvement Thrombocytopenia

Required 4 out of 11 , our patient 5 out of 11 Leucopenia + ANA Anti ds DNA _ Anti Sm Antiphospholipid antibody Low complement Required 4 out of 11 , our patient 5 out of 11

2015 ACR/EULAR DIAGNOSTIC CRITERIA FOR SCLERODERMA Skin thickening of fingers of both hands extending upto MCP joint(sufficient)/ 9 _ Finger tip lesions(digital ulcers)/2 + Puffy fingers / 2 Telangectasias/ 2 Abnormal nailfold capillaries/2 PAH/ILD(max score 2) Raynaud’s phenomenon/3 Anti Scl 70(max score 3) Required is 9 , our patient has score of 10

2010 ACR/EULAR CRITERIA FOR RA CRITERION SCORE JOINTS AFFECTED 1 Large joint 2-10 large joints 1 1-3 small joints 2 4-10 small joints 3 SEROLOGY Negative RF or ACPA Low positive RF or ACPA High positive RF or ACPA

Required score 6 or more, our patient 7. DURATION OF SYMPTOMS <6 Weeks >6 Weeks 1 ACUTE PHASE REACTANTS Normal CRP and ESR Abnormal CRP or ESR Required score 6 or more, our patient 7.

MCTD DIAGNOSTIC CRITERIA Kasukawa’s criteria Our Patient Raynaud’s or swollen fingers/hands + Anti U1 RNP autoantibodies _ SLE Signs/ symptoms Polyarthritis Facial rash Serositis - Lymphadenopathy Leucopenia Thrombocytopenia

Scleroderma signs / symptoms Dermatomyositis signs/symptom Sclerodactyly _ Pulmonary fibrosis Vital capacity <80% CO Diffusion <70% Esophageal hypomotility Dermatomyositis signs/symptom Muscle weakness + Increased CPK EMG Abnormalities

DIAGNOSTIC SCORING OF THE PATIENT SLE: 5/11 ACR Criteria. Scleroderma : patient having score of 10 which is diagnostic of having definite scleroderma. RA: Required is 6 or more, our patient has 7 MCTD: Fulfilling clinical criteria as the patient is having Raynaud’s phenomenon, SLE like features and dermatomyositis like features. Seronegative for anti U1 RNP antibodies. Hence the diagnosis of MCTD could not be established.

Final Diagnosis Overlap syndrome

TREATMENT NSAIDs STEROIDS NIFEDIPINE PPI

FOLLOW UP OF THE PATIENT Follow up of the patient was done 6 weeks after the initial therapy. There was no progression of any of the autoimmune disorders to a full blown form. Patient’s condition had improved significantly with the supportive management and initial treatment.

OVERLAP SYNDROME The term has been used when two or more autoimmune diseases occur in the same individual simultaneously. Example: The existence of Systemic lupus erythematosus, rheumatoid arthritis,scleroderma, dermatomyositis, polymyositis in various combinations.

SYSTEMIC LUPUS ERYTHEMATOSIS

DEFINITION SLE is a systemic,autoimmune disease in which tissues and multiple organs are damaged by pathogenic auto antibodies and immune complex formation

CLINICAL FEATURES : Skin involvement like malar rash , discoid rash Arthritis Oral ulcers Serositis (pleuritis or pericarditis) Renal involvement Neurologic disorder (seizures or psychosis) Hematologic disorder (hemolytic anemia, leukopenia, thrombocytopenia) Raynaud’s phenomenon

INVESTIGATIONS All baseline investigations. Complete autoimmune profile ESR CRP

MANAGEMENT Education of the patients regarding nature of illness. Supportive management like analgesics, NSAIDS, hydroxychloroquine. Steroids may be required in combination with immunosuppressants like methotrexate , azathioprine or MMF. Patients inadequately responding to standard therapy may given a trial of BELIMUMAB which targets B cell growth factors.

RHEUMATOID ARTHRITIS

DEFINITION It is a long lasting autoimmune disorder that primarily affects joints typically resulting in swollen, warm and painful joints. The hallmark of RA is inflammatory synovitis that presents in a symmetric distribution

CLINICAL FEATURES Typical presentation is with pain, joint swellings and stiffness of small joints of hands, feet and wrists. constitutional symptoms: fatigue, anorexia, weight loss, generalized weakness There needs to be involvement of multiple joints, but some joints are never involved in RA: • DIPs • Joints of the lower back

EXTRA ARTICULAR MANIFESTATIONS Cutaneous and vascular features Ocular involvement Cardiac and pulmonary involvement Neurological complications Vasculitis Hematological involvement Lymphatic involvement Amyloidosis , a rare complication.

To monitor disease damage INVESTIGATIONS To establish diagnosis: Clinical criteria ESR and CRP RA factor and anti CCP antibodies USG /MRI To monitor disease damage X-rays Functional assessment

MANAGEMENT General measures DMARD’s (Mainstay of management) Corticosteroids Biological therapy (high disease activity despite adequate treatment with DMARD’s)

SYSTEMIC SCLEROSIS

It is four times more common in females Generalized disorder of connective tissue affecting skin, internal organs and vasculature. T lymphocytes invading skin , abnormal fibroblast activation, increased extracellular matrix and thus resulting in symmetrical thickening, tightening and induration of skin and internal organs It is four times more common in females Progressive disease involving the skin and connective tissue which involves increased deposition of collagen in small arteries and connective tissue and sclerotic changes in skin and internal organs.

Patterns Limited cutaneous systemic sclerosis: affects face and distal limbs predominately Diffuse cutaneous systemic sclerosis: affects trunk and proximal limbs predominately Scleroderma (without internal organ involvement) tightening and fibrosis of skin

CLINICAL FEATURES: Diagnosis: Skin Musculosketal features Raynaud’s phenomenon GIT, Pulmonary and Renal involvement. Diagnosis: Mostly Clinically anti-scl-70 antibodies associated with DCSS anti-centromere antibodies associated with LCSS ANA positive in 90%

DERMATOMYOSITIS

DEFINITION It is an autoimmune disorder characterized by an inflammatory process that affects the skeletal muscles and the skin.

CLINICAL FEATURES Features of polymyositis i.e. symmetrical proximal muscle weakness. Characteristic skin lesions i.e. heliotrope rash, gottron’s papules which are scaly erythematous or psoriasiform plaques occurring over extensor surfaces of PIP & DIP joints. Periungual nailfold capillaries

INVESTIGATIONS Muscle enzymes (aldolase, CPK) EMG Muscle biopsy (gold standard) MRI (in case myositis is patchy and muscle biopsy is normal) CT chest/ abdomen if malignancy suspected.

MANAGEMENT Oral corticosteroids 1 mg/kg daily I/V steroids (if involvement of respiratory or pharyngeal muscles ) Immunosuppressive therapy

MIXED CONNECTIVE TISSUE DISEASE

DEFINITION This is an overlap condition in which there are clinical features of SLE , systemic sclerosis , myositis and Rheumatoid arthritis with the presence of anti U- 1 RNP antibodies. MCTD was first recognized by Sharp and colleagues in 1972

Clinical presentation EARLY FINDINGDS: Low grade fever Swollen hands Malaise , easy fatigability Arthralgias/arthritis Myalgias Raynaud's phenomenon

Unusual findings Neurological involvement like trigeminal neuralgias , aseptic meningitis Serositis Digital gangrene Pulmonary hypertension Polymyositis Esophageal hypomotility Hematologic abnormalities like leukopenia , thrombocytopenia Cardiac involvement

DIAGNOSTIC CRITERIA Common symptoms a. Raynaud’s phenomenon b. Swollen fingers or hands Features of SLE , systemic sclerosis , and polymyositis Anti-RNP antibody

LABORATORY STUDIES CBC Urine R/E Routine blood chemistry Muscle enzymes if myositis Lipase /amylase if pancreatitis Anti U1 RNP antibody Antinuclear antibodies High titer speckled fluorescent anti nuclear antibody is specific of MCTD (FANA)

Other immune studies Rheumatoid factor is frequently detected Antiphospholipid antibodies Other lupus specific antibodies are absent i.e. anti dsDNA C3 and C4 complement levels are more likely be depleted in lupus than in MCTD

IMAGING Chest radiography - for infiltrates, effusion cardiomegaly Echocardiography Ultrasonography/CT scanning MRI - Used to assess neuropsychiatric signs or symptoms

TREATMENT Arthritis/arthralgia :nonsteroidal anti-inflammatory drugs (NSAIDs) and hydroxychloroquine. Low-dose oral corticosteroids or low-dose methotrexate : refractory synovitis PPI : Reflux esophagitis Calcium channel antagonists : raynaud,s Phosphodiesterase inhibitors, endothelin receptor antagonists, or prostaglandins : pulmonary hypertension.

FOLLOW UP With stable disease approximately every 2-4 months and perform routine laboratory evaluation, including CBC count and chemistry studies. Patients with active disease are typically seen approximately every 3-6 weeks, depending on the severity of disease.

Undiffrentiated connective tissue disease The diagnosis of UDCTD is used to those patients with features strongly suggestive of autoimmune rheumatic diseases but who do not fulfill the criteria of any one of the disorders. Ex: Raynaud’s phenomenon, polyarthritis, rash, myalgias. This entity may evolve into a specific disease or may persists unchanged over years or may even disappear

CONCLUSION Various autoimmune disorders can coexist in a same individual even if they do not fit into diagnostic criteria of a broader term ie MCTD.They may progress into a full blown clinical form of any one of the disorder or may remain quiscent for a number of years. Patients who are seronegative for a particular disease cannot be excluded for not having a disease if they are fullfiling the clinical criteria.