WHO Classification of Lupus Nephritis Minimal Mesangial Glomerulonephritis - histologically normal on light microscopy but with mesangial deposits on electron microscopy CLASS II Mesangial Proliferative Lupus Nephritis - typically responds completely to treatment with corticosteroids CLASS III Focal Proliferative Nephritis - often successfully responds to treatment with high doses of corticosteroids CLASS IV Diffuse Proliferative Nephritis - mainly treated with corticosteroids and immunosuppressant drugs CLASS V Membranous Nephritis - characterized by extreme edema and protein loss CLASS VI Glomerulosclerosis

International Society of Nephrology/Renal Pathology Society (INR/RPS) 2003 Classification of Lupus Nephritis CLASS I Minimal Mesangial Lupus Nephritis - normal glomeruli by LM but mesangial immune deposits by IF CLASS II Mesangial Proliferative Lupus Nephritis purely mesangial hypercellularity of any degree or mesangial matrix expansion by LM, with mesangial immune deposits may be a few isolated subepithelial or subendothelial deposits visible by IF or EM, but not by LM CLASS III Focal Lupus Nephritis active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving <50% of all glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations III-(A) Active lesions: focal proliferative lupus nephritis III-(A/C) Active and chronic lesions: focal proliferative and sclerosing lupus nephritis III-(C) Chronic inactive lesions with glomerular scars: focal sclerosing lupus (LM – Light Microscopy, IF – Immunofluorescence Microscopy, EM – Electron Microscopy) Weening et. al. 2004. The Classification of Glomerulonephritis in Systemic Lupus Erythematosus Revisited. J Am Soc Nephrol 15:241-250.

International Society of Nephrology/Renal Pathology Society (INR/RPS) 2003 Classification of Lupus Nephritis CLASS IV Diffuse Lupus Nephritis active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis involving 50% of all glomeruli, typically with diffuse subendothelial immune deposits, with or without mesangial alterations this class is divided into: diffuse segmental(IV-S) lupus nephritis when 50% of the involved glomeruli have segmental lesions diffuse global (IV-G) lupus nephritis when 50% of the involved glomeruli have global lesions segmental is defined as a glomerular lesion that involves less than half of the glomerular tuft this class includes cases with diffuse wire loop deposits but with little or no glomerular proliferation IV-S (A) Active lesions: diffuse segmental proliferative lupus nephritis IV-G (A) Active lesions: diffuse global proliferative lupus nephritis IV-S (A/C) Active and chronic lesions: diffuse segmental proliferative and sclerosing lupus nephritis Active and chronic lesions: diffuse global proliferative and sclerosing lupus nephritis IV-S (C) Chronic inactive lesions with scars: diffuse segmental sclerosing lupus IV-G (C) Chronic inactive lesions with scars: diffuse global sclerosing lupus nephritis Weening et. al. 2004. The Classification of Glomerulonephritis in Systemic Lupus Erythematosus Revisited. J Am Soc Nephrol 15:241-250.

International Society of Nephrology/Renal Pathology Society (INR/RPS) 2003 Classification of Lupus Nephritis CLASS V Membranous Lupus Nephritis global or segmental subepithelial immune deposits or their morphologic sequelae by LM and by IF or EM, with or without mesangial alterations may occur in combination with class III or IV in which case both will be diagnosed shows advanced sclerosis CLASS VI Advanced Sclerosing Lupus Nephritis - 90% of glomeruli globally sclerosed without residual activity (LM – Light Microscopy, IF – Immunofluorescence Microscopy, EM – Electron Microscopy) Weening et. al. 2004. The Classification of Glomerulonephritis in Systemic Lupus Erythematosus Revisited. J Am Soc Nephrol 15:241-250.

3. Enumerate the side-effects of cyclophosphamide diarrhea lethargy chemotherapy-induced nausea and vomiting bone marrow suppression darkening of the skin/nails alopecia (hair loss) or thinning of hair changes in color and texture of the hair hemorrhagic cystitis Hemorrhagic cystitis is a frequent complication, but this is prevented by adequate fluid intake and Mesna (sodium 2-mercaptoethane sulfonate). Mesna is a sulfhydryl donor and binds acrolein. Reference: http://www.drugs.com/sfx/cyclophosphamide-side-effects.html

3. Enumerate the side-effects of cyclophosphamide carcinogenic, potentially causing transitional cell carcinoma of the bladder as a long-term complication lower the body's immune system cause temporary or (rarely) permanent sterility. Reference: http://www.drugs.com/sfx/cyclophosphamide-side-effects.html

Signs of an infection, such as chills or a fever Blood in the stool Some side effects with cyclophosphamide are potentially serious and should be reported immediately to a healthcare provider. These include but are not limited to: Signs of an infection, such as chills or a fever  Blood in the stool Blood in the urine (which can be a sign of bladder damage) Severe mouth sores Signs of an allergic reaction, including unexplained rash, hives, itching, and unexplained swelling. Severe nausea, vomiting, or diarrhea Decreased urination, which may be a sign of kidney damage Difficulty breathing or water retention, which may be signs of congestive heart failure Any unusual moles, skin sores that do not heal, or unusual lumps (which can be signs of new tumors or cancers) Reference: http://www.drugs.com/sfx/cyclophosphamide-side-effects.html

Clinical and radiographic manifestations of musculoskeletal TB

TB of Bones and Joints Weight-bearing joints Phemister’s Triad spine 40% hips 13% knees 10%ff Phemister’s Triad Juxta-articular osteoporosis Peripherally located osseous erosions Gradual narrowing of the intra-osseous space In the United States, tuberculosis of the bones and joints is responsible for ~10% of extrapulmonary cases. In bone and joint disease, pathogenesis is related to reactivation of hematogenous foci or to spread from adjacent paravertebral lymph nodes. While the upper thoracic spine is the most common site of spinal tuberculosis in children, the lower thoracic and upper lumbar vertebrae are usually affected in adults. Reference: Fauci. Braunwald. Kasper. Hauser. Longo. Jameson. Loscalzo. 2008. Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA

Pott’s Disease (Tuberculous Spondylitis) most dangerous form of musculoskeletal TB bone destruction, deformity, and paraplegia Progressive bone destruction, >2 adjacent vertebral bodies leads to vertebral collapse and kyphosis (due to collapse in anterior spine) Spinal canal narrowing: abscesses, granulation tissue or direct dural invasion leading to SC compression and neurologic deficits Reference: Fauci. Braunwald. Kasper. Hauser. Longo. Jameson. Loscalzo. 2008. Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA

Clinical Manifestations Back pain, stiffness thoracic and lumbosacral region most common Constitutional symptoms = fever, weight loss Most deadly complication = paraplegia due to abscess compressing the spinal cord Reference: Fauci. Braunwald. Kasper. Hauser. Longo. Jameson. Loscalzo. 2008. Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA

Radiographic Findings Lytic destruction of anterior portion of vertebral body Increased anterior wedging Collapse of vertebral body Reference: Emedicine. 2009. Pott’s Disease. Retrieved February 16, 2010 from http://emedicine.medscape.com/article/226141-overview

CT Scan provides better bony detail of irregular lytic lesions, sclerosis, disk collapse and disruption of bone circumference reveals early lesions and is more effective for defining the shape and calcification of soft-tissue abscesses. Reference: Emedicine. 2009. Pott’s Disease. Retrieved February 16, 2010 from http://emedicine.medscape.com/article/226141-overview

Radiographic Manifestation CT scan demonstrating destruction of the right pedicle of T10 due to Pott's disease Reference: Fauci. Braunwald. Kasper. Hauser. Longo. Jameson. Loscalzo. 2008. Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA

Tuberculosis of Hip and Knee Joints Unrecognized  joint destruction Hip joints Involves the head of the femur (common) Painful Knee joints Pain and swelling Diagnosis: biopsy, tissue culture and synovial fluid exam (thick in appearance, high protein concentration and variable cell count) Reference: Fauci. Braunwald. Kasper. Hauser. Longo. Jameson. Loscalzo. 2008. Harrison’s Principles of Internal Medicine, 17th Edition. McGraw-Hill. USA

Tuberculosis of the Hip femoral head has disappeared, the acetabulum is irregular and sclerotic, and there are cystic changes both in the femoral neck and around the joint. Lesion on femoral head and acetabulum Kissing Lesion: hallmark of TB infection Reference: Singh, Arun Pal. 2009. X-Ray of TB of Hip Joint. Retrieved February 16, 2010 from http://boneandspine.com/muculoskeletal-radiology/xray-of-tuberculosis-of-hip-joint/

calcified debris in the supra-patellar bursa A healed but badly damaged joint, with partial destruction of the upper end of the tibia, and a lot of new bone and loose fragments. There is calcified debris in the supra-patellar bursa. Reference: Palmer & Reeder. 2009. The Imaging of Tropical Diseases. Retrieved February 16, 2010 from http://www.isradiology.org/tropical_deseases/tmcr/chapter5/lymphadenopathy.htm

Clinical, laboratory, radiographic manifestations of genitourinary TB

Clinical Manifestations Local symptoms predominate Up to one third of patients may concomitantly have pulmonary manifestations Common symptoms include: Urinary frequency Dysuria Nocturia Hematuria Abdominal and Flank pain Harrison’s Principle of Internal Medicine, 17th ed. P1011-1012

Clinical Manifestations In females: May affect the fallopian tubes and the endometrium causing infertility, pelvic pain and menstrual abnormalities In males: Primarily affects the epididymis, producing a slight tender mass that may drain externally through a fistulous tract; orchitis and prostatitis. Harrison’s Principle of Internal Medicine, 17th ed. P1011-1012

Laboratory Manifestations Urinalysis: Pyuria and Hematuria Urine Culture: Pyuria but negative for common organisms causing UTI Culture of three morning urine specimens positive for Mycobacterium tuberculosis is a definitive diagnosis. Harrison’s Principle of Internal Medicine, 17th ed. P1011-1012

Radiographic Manifestations Intravenous pyelography Abdominal CT MRI Deformities, obstructions, calcifications and ureteral strictures are suggestive findings in genitourinary tuberculosis. Harrison’s Principle of Internal Medicine, 17th ed. P1011-1012

Side effects of anti-TB medications HREZ

Isoniazid Isoniazid-induced hepatitis-most common major toxic effect Peripheral neuropathy CNS toxicity-memory loss, psychosis,seizures Fever and skin rashes Drug-induced SLE Hematologic abnormalities Provocation of pyridoxine deficiency anemia Tinnitus Gastrointestinal discomfort Katzung, B, Basic and Clinical Pharmacology 10th ed., McGraw Hill 2007, page 773

Rifampicin Orange urine, sweat and tears Rashes Thrombocytopenia Nephritis Light-chain proteinuria Flu-like sydrome(fever, chills, myalgia, anemia and thrombocytopenia) Katzung, B, Basic and Clinical Pharmacology 10th ed., McGraw Hill 2007, page 774

Ethambutol Retrobulbar neuritis most common serious adverse event Loss of visual acuity and red-green color blindness Hypersensitivity syndrome consisting of cutaneous reaction (such as rash or exfoliative dermatitis) Fever and lymphadenopathy Katzung, B, Basic and Clinical Pharmacology 10th ed., McGraw Hill 2007, page 774 http://www.drugs.com/sfx/ethambutol-side-effects.html

Pyrazinamide Hepatotoxicity-major adverse effect Nausea Vomiting Fever hyperuricemia Katzung, B, Basic and Clinical Pharmacology 10th ed., McGraw Hill 2007, page 775

*Streptomycin Vertigo and hearing loss nausea, vomiting paresthesia of face rash fever Urticaria angioneurotic edema eosinophilia Katzung, B, Basic and Clinical Pharmacology 10th ed., McGraw Hill 2007, page 775 http://www.drugs.com/sfx/streptomycin-side-effects.html

Anti-TB regimen in special situations of liver disease, renal impairment, and pregnancy.

Liver disease Patients with pre-existing liver disease can receive the usual TB regimens provided that there is no clinical evidence of chronic liver disease, hepatitis virus carriage, a past history of acute hepatitis, current excessive alcohol consumption. However, hepatotoxic reactions to anti-TB drugs may be more common among these patients and should therefore be anticipated The first-line drugs HRZ are all associated with hepatotoxicity. Pyrazinamide is the most hepatotoxic Treatment of tuberculosis: guidelines - 4th ed. WHO http://whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf

If the serum AST level is more than 3 times normal before the initiation of treatment, the following regimens should be considered . • Two hepatotoxic drugs (rather than the three in the standard regimen): 9 months of HRE 2 months of HRSE followed by 6 months of HR 6–9 months of RZE. • One hepatotoxic drug: 2 months of HES, followed by 10 months of HE • No hepatotoxic drugs: 18–24 months of streptomycin, ethambutol and a fluoroquinolone. The more unstable or severe the liver disease is, the fewer hepatotoxic drugs should be used. In general, patients with chronic liver disease should not receive pyrazinamide. All other drugs can be used, but close monitoring of liver enzymes is advised.

Renal impairment The recommended initial TB treatment regimen for patients with renal failure or severe renal insufficiency is 2 months of HRZE, followed by 4 months of HR. Isoniazid and rifampicin are eliminated by biliary excretion, so no change in dosing is necessary. There is significant renal excretion of ethambutol and metabolites of pyrazinamide and doses should therefore be adjusted. Three times per week administration of these two drugs at the following doses is recommended: pyrazinamide (25 mg/kg), and ethambutol (15 mg/kg) Treatment of tuberculosis: guidelines - 4th ed. WHO http://whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf

Renal impairment While receiving isoniazid, patients with severe renal insufficiency or failure should also be given pyridoxine in order to prevent peripheral neuropathy. Streptomycin should be avoided in patients with renal failure because of an increased risk of nephrotoxicity and ototoxicity. If streptomycin must be used, the dosage is 15 mg/kg, two or three times per week, to a maximum of 1 gram per dose, and serum levels of the drug should be monitored.

Pregnancy Women of childbearing age should be asked about current or planned pregnancy before starting TB treatment. A pregnant woman should be advised that successful treatment of TB with the standard regimen is important for successful outcome of pregnancy. With the exception of streptomycin, the first line anti-TB drugs are safe for use in pregnancy streptomycin is ototoxic to the fetus and should not be used during pregnancy. Pyridoxine supplementation is recommended for all pregnant women taking isoniazid Treatment of tuberculosis: guidelines - 4th ed. WHO http://whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf