CSTAR CASE STUDIES: BLOCK F Type 3 Hypersensitivity Reaction

Transcription

1 CSTAR CASE STUDIES: BLOCK F Type 3 Hypersensitivity Reaction Setting: ER Mr. Smith I ve just felt so weak for so long, and I ve lost so much weight, and now I m having trouble breathing it s affecting my work! HPI: Ms. Smith is a 36-year-old woman working full time as a secretary. She presents to the hospital with a 6-month history of generalized weakness and significant weight loss of 20lbs (over past 4 mos). Over the past two weeks she has had progressive worsening of dyspnea and cannot do house/yard work because of pain in elbows and knees. She has recently had to take time off work because she cannot type and sit for prolonged periods of time. Known Allergies: none. Habits: No smoking, drug, or alcohol use. Meds: No meds. PMHx: Has been treated for past episodes of leukopenia. Says she has had episodes of high blood pressure when shes gone to pharmacy to check. Mild fever in past but never that high. (If student ask about urine, say its darker and shes peeing more at night) Leukopenia Tx was Neupogen (filgrastim), a form of G-CSF (protein that acts on bone marrow to boost WBC production) FHx: unremarkable. Physical Exam: Ms. Smith present with mucosal pallor, shows no signs of cyanosis, digital clubbing, pitting edema, skin rash, or joint deformities BP: 128/70 HR: 88 bpm Resp. rate: 24 breaths/min Breath sounds: Decreased breath sounds and dullness to percussion were noted on the left base Abdomen: Examination and palpation of abdomen was non-tender to palpation. Palpation of lymph nodes revealed rubbery axillary and inguinal lymphadenopathy Cardiovascular and Neurological: Unremarkable ROM: Painful ROM in bilateral elbows and knees. All other joints WNL Labs: Anemic (hemoglobin 105, norm: ), leukopenic (2.9, norm x 10 9 /L), elevated blood urea nitrogen, elevated creatinine. Serology: high anti-nuclear antibody (ANA), so also tested for anti-double stranded DNA antibody, anti-smith antibody titers (both high). Discussion Questions: 1) What symptoms here have significance, why? What do they indicate? Why the weight loss? 2) What investigations do you order, why? What is it we are concerned about? What gold standard test should be performed? a) What kind of hypersensitivity reaction is Lupus? 3) What other signs/symptoms might you see/ask about? What are the ACR criteria for SLE? 4) What can be done for the muscle weakness? What other treatments could be recommended? 5) What kinds of lupus exist?

2 1) Signs & Symptoms: Decreased breath sounds + dullness signs of inflammation of tissue lining lungs Inflammation of joints (esp for her age) Past leukopenia Dark urine + more frequent nocturnal urination Renal disfunction o Leading to hypertensive symptoms. Weight loss (and fever) could be due to thyroid inflammation/malfunction (autoimmunity against thyroid), but could also be decreased appetite from weakness. Fever is a non-specific symptom. 2) What investigations do you order, why? What would be considered a gold standard for your suspected Dx? BUN and Creatinine check renal function ANA if high and fits with clinical picture order anti-ds DNA antibody and anti-smith antibody titers Gold standard: Renal biposy. In lupus nephritis, what features on renal biopsy point towards and autoimmune pathogenesis? o Presence of immune complexes: several antibodies (IgM, IgG) and complements (C3,C4 etc.) together with some antigen, location of these will give clues o Inflammatory cells + their location points to diff types of disease. o Anti-DNA antibodies have been found in the immune complexes, implying a potential pathological role of these antibodies in lupus nephritis a) Lupus is a Type 3 hypersensitivity: immune-complex mediated rxn. 3) What other signs/symptoms might you see/ask about? What are the ACR criteria for SLE? On physical exam: malar rash (butterfly rash), discoid rash photosensitivity, oral ulcers Neuro signs CNS manifestations of systemic lupus erythematosus (CNS lupus): neuropsychiatric events can occur in ~45% (range 14-75%) of cases Gi involvement Dry mouth or eyes? o some people with lupus develop Sjogrens disease, another autoimmune disorder. Sjogrens causes the glands responsible for tears and saliva to malfunction, and lymphocytes can accumulate in the glands. In some cases, women with lupus and Sjogrens may also experience dryness of the vagina and skin. ACR mnemoic of SLE diagnostic criteria (need 4/11) The following are the ACR diagnostic criteria in SLE, presented in the "SOAP BRAIN MD" mnemonic: Serositis - Pleurisy, pericarditis on examination or diagnostic electrocardiogram (ECG) or imaging Oral ulcers - Oral or nasopharyngeal, usually painless; palate is most specific Arthritis - Nonerosive, 2 or more peripheral joints with tenderness or swelling Photosensitivity - Unusual skin reaction to light exposure Blood disorders - Leukopenia (< cells/µl on >1 occasion), lymphopenia (< 1500 cells/µl on >1 occasion), thrombocytopenia (< cells/µl in the absence of offending medications), hemolytic anemia Renal involvement Based on presence of proteinuria (>0.5 g/day or 3+ positive on dipstick testing) or cellular casts (including red blood cells [RBCs], hemoglobin, granular, tubular, or mixed) [96] or based on the opinion of a rheumatologist or nephrologist [96] Antinuclear antibodies (ANAs) - Higher titers generally more specific (>1:160); must be in the absence of medications associated with drug-induced lupus. A positive ANA test means autoantibodies are present. By itself, a positive ANA test does not indicate the presence of an autoimmune disease or the need for therapy. Immunologic phenomena - dsdna; anti-smith (Sm) antibodies; antiphospholipid antibodies (anticardiolipin immunoglobulin G [IgG] or immunoglobulin M [IgM] or lupus anticoagulant); biologic false-positive serologic test results for syphilis, lupus erythematosus (LE) cells (omitted in 1997 revised criteria)

3 Neurologic disorder - Seizures or psychosis in the absence of other causes Malar rash - Fixed erythema over the cheeks and nasal bridge, flat or raised Discoid rash - Erythematous raised-rimmed lesions with keratotic scaling and follicular plugging, often scarring In patients with high clinical suspicion and/or high ANA titers, additional testing is indicated. This commonly includes evaluation of antibodies to dsdna, complement, and ANA subtypes such as Sm, SSA, SSB, and ribonucleoprotein (RNP) (often called the ENA panel), as well as screening anticardiolipin antibodies, lupus anticoagulant, and +/- beta-2 glycoprotein antibodies. 4) What can be done for her muscle weakness? What other treatments might we recommend? - Regular exercise helps prevent muscle weakness and fatigue. Careful control and restriction of some activities can help manage exacerbations. - 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. Immunosuppressives can also be used if the patient has an inadequate response or excessive sensitivity to corticosteroids - Treat hypertension aggressively. On the basis of beneficial effects in other nephropathies, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have been routinely used to treat proteinuria in lupus nephritis. - Alter the diet according to the presence of hypertension, hyperlipidemia, and 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 supplementation to prevent osteoporosis if the patient is on long-term corticosteroid therapy, and consider adding a bisphosphonate (depending on renal function). - 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. - Prevention: stressors, smoking, alcohol, sun exposure (photosensitivity). 5) What kids of lupus exist? - Systemic lupus erythematosus (SLE) This is the disease often simply referred to as lupus. The word "systemic" refers to the fact that connective tissues throughout the body are affected; "erythematosus" is a clinical state in which red, raised patches develop on the skin. When referring to lupus elsewhere in this chapter, we are referring to this form of the disease. - Discoid lupus erythematosus This form of lupus is distinct from SLE in that the symptoms are only skin related; discoid lupus erythematosus causes a red rash ("erythematosus"), often developing on the face and/or scalp. People with discoid lupus often also have SLE, or develop SLE in the future. - Drug-induced lupus Certain medications can potentially cause lupus, but the condition generally goes away after stopping the triggering drug. The medications that can possibly cause drug-induced lupus include some oral birth-control drugs, certain blood pressure-lowering drugs, and antibiotics and antifungal medications. o Specific drugs most frequently associated with drug-induced lupus include: Procainamide antiarrhythmic drug Hydralazine blood pressure lowering drug Quinidine - antiarrhythmic drug - Neonatal lupus As the name indicates, this form of lupus develops in newborn infants. This form of lupus is quite rare, and is caused by autoantibodies being transmitted from a mother with lupus to the baby (White 1994). Although most of the babies born of women with lupus are healthy (Womenshealth.gov 2011), more than half of infants with neonatal lupus have problems with their skin, heart, and/or gallbladder (Silverman 2010; Wisuthsarewong 2011). Neonatal lupus may

4 spontaneously resolve over the first few months of life, but can sometimes cause serious complications. Death occurs in approximately 10% of neonatal lupus cases, the major causes of which are typically pneumonia or heart complications (Wisuthsarewong 2011). Hypersensitivity Classification There are four types of hypersensitivity reactions, each mediated by a different mechanism 1-4: type 1 hypersensitivity: immediate reaction IgE mediated binds to Fc membrane receptor on mast cells and interacts with corresponding antigen mast cell degranulation occurs on following exposure 8 urticaria asthma allergy/anaphylaxis type 2 hypersensitivity: antibody mediated reaction IgG/IgM mediated causes cell destruction and disrupts cell function 5 autoimmune haemolytic anaemia Goodpasture syndrome rheumatic heart disease 9 type 3 hypersensitivity: immune-complex mediated reaction IgG/IgM mediated antibody-antigen Immunocomplex deposition these can activate complement, cause release of chemotactic and clotting factor and trigger phagocytosis vasculitis 6 systemic lupus erythematosus (SLE) hypersensitivity pneumonitis type 4 hypersensitivity: cell-mediated reaction 'delayed' hypersensitivity T-helper cells secrete various different cytokines resulting in different immune reactions interferon y secreted by T-helper type 1, which activate macrophages leading production of complement-fixing antibody isotypes stimulating inflammatory responses CD8+ T-cell mediated killing of cells expressing reactive antigen in association with MHC-1 IL-4, IL-5, IL-13 secreted by T-helper type 2 stimulate B cell activation and production of immunoglobulins (IgE), mast cell and eosinophil reactions and macrophage deactivation other T-cells contain granules performing cytotoxic functions by the release of perforin/granzymes directly killing the infected cells 7 contact dermatitis coeliac disease

5 transplant rejection type 1 diabetes multiple sclerosis