CASE OF A WOMAN WITH SYSTEMIC DISEASE Dr ENIDA XHAFERI

CASE PRESANTATION This is the case of a 30 years old woman who developed a wide range of clinical manifestations and symptoms over a period of 12 months.

Chief complains on admission Severe fatigue Symmetrical non erosive arthritis of the knee, carpal and proximal inter phalangeal joints Myalgia and muscle weakness Photosensitivity, described as development of a skin rash as an unusual reaction to sunlight Malar rash in the form of a flat fixed eritema over malar eminencies. Macupapular lesions on both arms Painful buccal ulcerations Diffuse hair loss Periungal erythema Headaches and mood changes

History Patient explains that she reported her problems to the family physician who formed his own diagnose and referred the case to the local rheumatologjist for more specialized follow up. He gave her also a short course of low dose glucocorticoids, nonsteroidal antiinflamatory steroids, calcium preparations and vitamins to control the immediate pathologic symptoms.

History Patient states that in the beginning her symptoms were mild which did not prompt an immediate visit to the specialist ( she occupied herself with work and family instead…!). She responded well to the GP therapy and she felt better until recently, when her health status has deteriorated considerably and she has observed also the development of edemas in her feet and “redness” over her fingers. At this moment she thought that it would be wise to go to the hospital.

ADITIONAL INFORMATION Patient does not have close family members with known rheumatic or musculoskeletal disorders, is married and has had one natural vaginal delivery. She has not been exposed to known toxins lately, does not use tobacco, alcohol, or illicit drugs, has not received any new medications and has no drug allergies.

PHYSICAL EXAMINATION Vital Signs and General Examination: Blood pressure 150/100 mm Hg; heart rate 110 beats/minute; respiratory rate 18 breaths/minute; T 37.5° C, Normostenic individual. Patient feels weakened and fatigued and sweats a lot. Mental status: Frequent headaches, distressed face, reduced concentration span and mild seizures. She states that lately she has had frequent mood swings and sleep disorders. Respiratory System : Normal vesicular respiration throughout, free lungs, no wheezing Cardiovascular System: Heart rate and rhythm was regular; normal S1 and S2 sounds with no murmurs, audible rubs, or positional substernal chest pain Abdomen: Abdomen was soft, not tender, and not distended, Blumberg (-)

Physical examination Gastrointestinal System: Normal bowel sounds, liver is palpated 2 cm under right costovertebral angle, no spleen enlargement. Patient relates that she experiences frequent bouts of dispnea, pyrosis and has other digestive disorders, and weight loss. Genital & Urinar System: Mild edema on the feet and face. Pasternacki (+) on both sides. Mucocutaneal lesions : Malar rash, photosensitivity, periungal eritema, oral lesions (punched out painful ulcers), presence of a reddish/cianotic eritematous pattern on the surface of both arms. Hair loss

Physical examination Musculoskeletal manifestations Knee, radiocarpal, proximal Inter phalangeal joints arthritic, tender, mildly swollen, and painful when pressed. Morning stiffness (lasting several minutes) Mialgia Back ache

HOSPITAL COURSE

ORDERED EXAMINATIONS Complete blood cell counts Urinalysis Kidney and liver function tests Total glicemia Azotemia + creatinemia Fibrinogen level ANA Rheumatoid factor C3 and C4 levels LE cell 24 hours diuresis Lipidic profile 24 hours albumin eskretion

Lab Test Results Blood Test Results: RBC 4650000/mm³; Hg 10.8 g/dl; HCT 40.2 %; MCV 86.5 g/l; MCH 29.7 pg/bl; MCHC 34.3 gr %;  PLT 145000/mm³;  WBC 3500/mm³;  ES 48 mm/h,  CRP 2 mg/dl. Biochemical Test Results : Glucosis 98 mg/ dl;  Urea 50.7 mg/dl;  Creatinin 2.4 mg/dl; ALP 11 U/L, AST 22; Total Bilirubin 0.7 mg/dl; Total Protein 6.7 mg/; Fib 450 mg/dl; Total Cholesterol 319 mg/dl;  Triglicerids 270.2 mg/dl;  Albumin 2 g/dl.

Immunologic Test Results Anti nuclear Antibodies (ANA) : (+) 1:650, homogenous/rim pattern Anti ds DNA antibodies : (+) IgG anticardiolipin antibodies (-) IgM anticardiolipin antibodies (-) Anti Ro antibodies : (-) Anti Sm antibodies : (-) C3 50 mg/dl (M: 97 –157 mg/dl)  C4 : 6 mg/dl (M:16.2 –44.5 mg/dl)  Rheumatoid Factor: (-) Some Anti-Nuclear antibody patterns seen on indirect immunoflurescence assays Homogenous Speckled Peripheral Centromere

Urinalysis Urine strip Albumin 6 g/dl Red blood cells/hpf 32 White blood cells/hpf 25 Hialine casts + Granular casts + Epitelial casts + 24 hours urine collection analysis Proteinuria 6 g/24 hours Creatinin 800 mg

A-P hands and L-L lumbar x-rays Unremarkable outcome

Questions What do you think would be the diagnosis in this case? What other examinations would you request? What kind of treatment would you select (low dose therapy or aggressive regimens with high dose glucocorticoids and cytotoxics) How would you monitor treatment response?

Revised criteria for classification of SLE Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Neurological disorders Immunologic disorders Renal disorders (proteinuria >0.5g/d or 3 + if quantification non performed or urine cellular casts Hematological disorders Anti nuclear antibody Lupus diagnosis is sure when at least 4 of these criteria are met

Results of the consultation with the nephrologist Nephrotic syndrome in the terrain of LES present (proteinuria, hematuria, hypoalbuminemia, hyperlipidemia edema), NIH protocol to be considered. Use ACE inhibitors for HTA and proteinuira. Renal biopsy indicated Recommended renoprotective treatment -Ramiprili 5 mg 1 tab per day -Dipyridamoli 75 mg 3x1 tab per day -Atorvastatini 20 mg 1 tab in the evening -Lasixi 40 mg

Renal involvement WHO Classification Class I - Minimal mesangial lupus nephritis Class II - Mesangial proliferative lupus nephritis Class III - Focal lupus nephritis Class IV - Diffuse lupus nephritis Class V - Membranous lupus nephritis Class VI -Advanced sclerosing lupus Renal biopsy showed the presence of Class IV G- A Lupus Nephritis

Treatment objectives for lupus nephritis Corticosteroid therapy should be instituted if the patient has clinically significant renal disease. Use immunosuppressive agents, particularly cyclophosphamide, azathioprine, or mycophenolate mofetil, if the patient has aggressive proliferative renal lesions, as they improve the renal outcome. They can also be used if the patient has an inadequate response or excessive sensitivity to corticosteroids. Treat hypertension aggressively. Consider angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) if the patient has significant proteinuria without significant renal insufficiency. Restrict fat intake or use lipid-lowering therapy such as statins for hyperlipidemia secondary to nephrotic syndrome. Restrict protein intake if renal function is significantly impaired. Administer calcium and vitamin D supplementations to prevent osteoporosis if the patient is on long-term corticosteroid therapy and consider adding a bisphosphonate. Avoid drugs that affect renal function, including nonsteroidal anti-inflammatory drugs (NSAIDs), especially in patients with elevated creatinine levels. Nonacetylated salicylates can be used to safely treat inflammatory symptoms in patients with renal disease. Patients with active lupus nephritis should avoid pregnancy, as it may worsen their renal disease.

Proliferative glomerulonephritis (DPGN) induction therapy protocols -NIH protocol: monthly pulse CYC, 0.75 g/m2, for 6 months and oral prednisone (PDN) 0.5 mg/kg per day for 4 weeks. PDN is tapered every other week and than day until a maintenance dose of 0.25 mg/kg every other day or the minimal dose required to control disease activity. - Euro-lupus nephritis protocol: 6 fortnightly CYC pulses at a dose of 500 mg. Corticosteroids were administered as 3 iv pulses of 750 mg of methylprednisolone (MP) followed by PDN 0.5 mg/kg/day for 4 weeks, tapered by 2.5 mg every 2 weeks to a maintenance dose of 5-7.5 mg/day. - Oral CYC protocols: CYC is administered at doses ranging from 1 to 2 mg/kg/day for 3 to 12 months. The most recently published protocol consisted in the administration of oral CYC for 6-9 months with PDN 0.5-1 mg/kg/day for 6-8 weeks, followed by tapering to a maintenance dose of 5-10 mg/day .

Medications used in this case - Induction phase Prednisone (PDN) 0.5 mg/kg per day (60 mg for patients weighing less than 80 kg) for 4 weeks, than 50,40,30 mg for the consecutive months . A new tapering regimen by 5 mg on alternate days is started at this point until the minimal dose required to control disease activity is reached. Cyclophosphamide Monthly pulse of 0.75 g/m2, for 6 months usually administered with antiemetic agents and may be administered with mesna. Response within 3-6 months Maintenance phase Azathioprine : 2-3 mg/kg/d PO single or divided dose. Initial: 1 mg/kg/d; increase depending on clinical and hematologic response and toxicity

Final comments Disease activity is checked through measurement of proteinuria, complement levels, anti ds-dna antibodies titer, and serum creatinine levels. At the third month of treatment the patient has developed some minor treatment side effects but her biologic indexes are improved.