What s New in Rheumatology Update in Rheumatology Chapter I: Clinical Case ERCP. Chapter I: Newly recognized disease

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1 What s New in Rheumatology 2012 Chapter I: Newly recognized disease Update in Rheumatology 2012 Chapter II: Newly renamed disease Jonathan Graf, MD Associate Professor of Medicine, UCSF Division of Rheumatology SFGH Chapter III: New disease treatments Most common disease: Gout One of most rare: ANCA vasculitis Chapter I: Clinical Case ERCP 65 year old male with a history of cholangitis six months earlier presents with chronic worsening or vague abd pain and pruritis. PE exam is normal except for mild scleral icterus. Labs are normal except for modestly elevated alkaline phosphatase, and MRCP followed by ERCP clearly suggest a diagnosis of sclerosing cholangitis. Stricture 1

2 Question The American Association for the Study of Liver Diseases (AASLD) recommends which of the following next steps: A. Check a serum IgG4 level B. Perform a liver biopsy C. Initiate treatment with corticosteroids D. Antibiotic prophylaxis for all PSC patients to prevent bacterial cholangitis 33% 33% 15% 18% A. B. C. D. Question The American Association for the Study of Liver Diseases (AASLD) recommends which of the following next steps: A. Check a serum IgG4 level B. Perform a liver biopsy C. Initiate treatment with corticosteroids D. Antibiotic prophylaxis for all PSC patients to prevent bacterial cholangitis IgG4-Related Systemic Disease (IgG4-RSD) IgG4-RSD Increasingly recognized syndrome of unknown etiology Collection of organ-specific disorders that share common clinical, serologic, and pathologic features Unifying concepts: Sclerosing/fibrotic disease with typical storiform pattern Tumefactive lesions (can mimic malignancy clinically and even pathologically) Lymphoplasmocytic cell infiltrate enriched in IgG4+ plasma cells Elevated serum IgG4 levels in majority but not all patients Allergic/atopic diathesis (eczema, atopy, asthma) 2

3 IgG4 Related Systemic Disease: Is it a new disease or a newly recognized disease? 1995: Autoimmune pancreatitis(aip) first described in Japan 2001: Some AIP patients found to have elevated serum levels of IgG4 Led to recognition of two distinct types of AIP Type I classical AIP patients had elevated IgG4 2003: Extra-pancreatic manifestations demonstrated in patients with Type I AIP Similar histopathology IgG4 Related Systemic Disease: Is it really a new disease? Many diseases once thought of as distinct illnesses are increasingly recognized as organ-specific manifestations of IgG4-RSD (partial list) Some of these diseases have been recognized as distinct clinical entities for over 100 years Autoimmune Pancreatitis (1995) Sclerosing cholangitis Fibrosing subset of Hashimoto s thyroiditis and Riedel s thyroiditis Retroperitoneal fibrosis Chronic sclerosing Aortitis and Chornic Inflammatory Aortitis Sjogren s syndrome like sialadenitis (Mikulicz s disease) Overall Clinical Features 2-3 times more prevalent in men than women Majority over age of 50 Subacute onset and course in majority Patients usually without constitutional symptoms Modest if any elevations in CRP Frequently diagnosed incidentally on imaging or pathology specimen Clinical Features Focal presentation in affected organ Tumor like masses mimicking malignancy Pancreatic, renal, orbital, salivary gland, hepatic masses Diffuse enlargement of an organ Inflammation and sclerosis/fibrosis of an organ, duct, or retroperitoneal tissue Multi-organ involvement (60-90%) Is often subclinical but can progress insidiously Involvement of multiple organs occur concomitantly or sequentially 3

4 IgG4-RSD: Organ Specific Manifestations Organ Specific Manifestations: Autoimmune Pancreatitis 6% of ALL cases of chronic pancreatitis in Japan are thought to be related to AIP 11% of 245 patients at Mayo clinic who underwent pancreatic resection for benign reasons had AIP Type I AIP associated with IgG4-RSD Classical AIP and is most prevalent form Autoimmune Pancreatitis Type I Can present as focal mass or localized inflammation, or as diffuse swelling, inflammation, and fibrosis AIP: Histopathology Periductal lymphoplasmaticytic inflammation Obliterative phlebitis with cartwheeling fibrosis Diffuse swelling and infiltration of pancreas Vlachou P A et al. Radiographics 2011;31:

5 Disease specific Antibody?? Frulloni et al. NEJM 2009 Antibody crossreacts with H. pylori peptide and antigen in pancreatic acini 95% of AIP patients had antibody vs. 10% of patients with pancreatic cancer 54% of patients had elevated levels of IgG4 Article is fuzzy about who had type I vs Type II AIP Remains controversial Sclerosing Cholangitis Variant 79% of patients with AIP had IgG4-RSD associated sclerosing cholangitis in Japanese cohort Male predominant Older age (two decades older than PSC patients) Not associated with ulcerative colitis and IBD Unlike PSC, IgG4-RSD SC is generally steroid responsive Reasoning behind AASLD s recommendations to check serum IgG4 level (despite its shortcomings) IgG4-RSD Sclerosing Cholangitis ERCP appearance can look like PSC but It tends to involve lower common bileduct more often Histopathology with lymphoplasmacytic Inflammation and transmural fibrosis Originally described as separate diseases > 100 years ago Chronic Sialadenitis Present in 24% of patients with AIP in Japanese cohort Two forms: Bilateral painless symmetrical swelling of lacrimal/salivary glands: Mikulicz s disease IgG4 staining plasma cells Frequently misdiagnosed as Sjogren s Syndrome (SS) variant Chronic sclerosing sialadenitis with unior bilateral submandibular gland enlargement (kuttner tumor) Frequently misdiagnosed as a salivary gland tumor Clues to distinguish IgG4-RSD from SS Male predominance Older age onset Seronegative (SSA/SSB) Steroid responsiveness 5

6 Retroperitoneal Fibrosis Generally presents non-specifically with constitutional symptoms or sequelae of obstruction (eg. ureteral or aortic ) Thick retroperitoneal fibrotic mass Earlier cases may be more cellular/ later cases may be more fibrotic Lymphoplasmacytic infiltrate enriched with IgG4 plasma cells and phlebitis (venulitis) Other organ involvement (Not complete list) Riedel s thyroiditis Chronic inflammatory and fibrosing disease often associated with AIP I, sclerosing cholangitis, retroperitoneal fibrosis Sclerosing variant of Hashimotos thyroiditis Aortitis and periaortitis Tubulointerstitial nephritis Prostatitis Misdiagnosis Failure to recognize and diagnose can lead to: Disease progression, irreversible fibrosis, and organ damage Unnecessary surgical procedures Whipple for suspected pancreatic cancer Surgery for cholangiocarcinoma Removal of orbital pseudotumors Thoracotomies Diagnosis: Utility of Serum IgG4 Levels Elevated serum IgG4 present in majority but not all patients Approximately 70% have elevated IgG4 Higher serum IgG4 titers may have more specificity for diagnosis Elevated IgG4 neither necessary nor sufficient to make diagnosis Helpful in suggesting the diagnosis (AASLD guidelines for sclerosing cholangitis) 6

7 Identification of IgG4 Plasma Cells in Path Specimens Presence of IgG4 positive plasma cells in tissue is necessary but neither specific nor sufficient to confirm diagnosis Characteristic Pathology is Diagnostic The larger the ratio of IgG4 staining plasma cells to other plasma cells in a specimen may be more suggestive of IgG4-RSD 1. Lymphoplasmacytic infiltration of tissue fibrosis with cartwheeling fibroblasts 3. Obliterative Phlebitis 2. Elevated numbers of IgG4 plasma cells Clinical Course Some patients can have spontaneous remissions (but many of those relapse) Others progress to major tissue damage and organ failure Most often subacute-chronic course Progressive fibrosis and organ distortion/destruction Cirrhosis and portal hypertension Retoriperitoneal fibrosis Aortic aneurisms Cholangitis can lead to hepatic failure more quickly Tumefactive lesions can lead to obstruction Possible increased malignancy risk Lymphoma, GI clear cell carcinoma, lung cancer, salivary gland cancer Treatment Not all patients need to be treated (painless lymphadenopathy) Most symptomatic cases of organ involvement should be treated to prevent progression to tissue destruction Most manifestations are responsive to corticosteroids 7

8 IgG4-RSD/Sclerosing Cholangitis: Treatment with Corticosteroids Corticosteroids and Other Therapies Failure to treat in many patients can lead to irreversible fibro-sclerosis and organ damage Patients can usually be tapered over the course of several months Some patients will relapse Experimental therapy with anti-b lymphocyte therapy Rituximab has shown some promise Symptom-specific therapy (e.g. stenting biliary strictures) Before After Chapter II: Case 36 year old female is admitted to the hospital with hemoptysis, respiratory distress, and acute kidney injury. She is taking no medications, is married, and has no children. Necrotizing Glomerulonephritis Her exam is significant for hypoxemia, and hypertension and her workup includes CXR with bilateral pulmonary nodules and infiltrates and an elevated creatinine with hematuria and dysmorphic RBC s. Her urine tox screen is negative and C- ANCA and Proteinase-3 antibodies are positive. Kidney biopsy reveals a pauci-immune necrotizing glomerulonephritis. Chest CT: Multiple Pulmonary Nodules And Ground Glass Opacities 8

9 Apologies!!! Question Chapter II: A Renamed Disease! This patient s diagnosis is most consistent with: A. Wegener s Granulomatosis B. Microscopic polyangiitis C. Systemic Lupus Erythematosus D. None of the Above 63% 9% 14% 14% Apologies!!! Chapter II: A Renamed Disease! This patient s diagnosis is most consistent with: A. Wegener s Granulomatosis B. Microscopic polyangiitis C. Systemic Lupus Erythematosus D. None of the Above A. B. C. D. Granulomatosis with Polyangiitis (GPA) Friedrich Wegener: German pathologist credited with describing the disease (died in 1990) Wegener s past ties to nazi party (1932) and work near Jewish Ghetto of Lodz have become more clearly understood in recent years 2011: Led to renaming of WG as GPA by major medical organizations including the ACR Case continued The patient is initially treated with high dose pulses of IV corticosteroids and begins to improve. However when cytotoxic therapy with oral cyclophosphamide is recommended, she expresses concern over her risks of becoming infertile, and she strongly desires to have a child in the next few years. This patient does have this disease!! 9

10 Question Which of the following statements is not correct? A. Risk of premature menopause resulting from cytoxan is dose and age-dependant B. Corticosteroids alone are not sufficient therapy to treat this disease C. Cytotoxic therapy should not be delayed for several months while the patient undergoes egg harvesting and cryopreservation D. Oral Cyclophosphamide is the only therapy approved to treat GPA 8% 27% 23% 42% A. B. C. D. Question Which of the following statements is not correct? A. Risk of premature menopause resulting from cytoxan is dose and age-dependent B. Corticosteroids alone are not sufficient therapy to treat this disease C. Cytotoxic therapy should not be delayed for several months while the patient undergoes egg harvesting and cryopreservation D. Oral Cyclophosphamide is the only therapy approved to treat GPA Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis Rituximab, B-cells, and ANCA Antineutrophil cytoplasmic antibodies are possibly implicated in pathogenesis or propagation/potentiation of ANCA-vasculitis Rituximab is a selective B-cell depleting antibody (anti- CD20) Possibility to remove ANCA by eliminating B-cells that would replace short-lived ANCA producing plasma cells Other possible mechanisms by which B-cells might be implicated in ANCA vasculitis 10

11 RAVE Study Multicenter, randomized, double dummy, double blinded placebo controlled non-inferiority trial Oral Cytoxan (Gold standard) vs. Rituximab Both regimens given with corticosteroids Included patients with both GPA and MPO (microscopic polyagiitis) as well as patients with relapsing disease Primary outcome: remission at 6 months free of glucocorticoid use (won t get into specifics of how remission defined). 197 patients enrolled RAVE: Summary 64% patients in rituximab arm reached endpoint vs. 53% in cytoxan arm (p<0.001) Comparable non-inferiority for GPA and MPA Comparable non-inferiority for alveolar hemorrage or major renal disease Ritux more effective for relapsing patients to achieve primary endpoint (67%) vs. cytoxan (42%) (P=0.01) No difference in Adverse Events (surprising) Our patient was concerned about fertility, not infections! FDA approval for rituximab to treat both GPA and MPA in 4/2011 Chapter III: New Treatments for an Ancient Disease Therapy for Gout Divided into two distinct categories Treatment for Acute Gout Flares Abrogate attacks and return to inter-critical period Anti-inflammatory focus Henry VIII Benjamin Franklin Chronic Gout Therapy Reduce number of severity of future flares Shrink or reduce tophi and prevent articular destruction T. Rex 11

12 Acute Gout: Little has changed Therapy is aimed at reducing the severity and duration of symptoms and reaching the inter-critical period sooner NSAIDs Effective and rapid relief of symptoms Contraindicated in patients with GI, Renal, or hypersensitivity concerns Corticosteroids Intraarticular Systemic Colchicine Recently Approved for Acute Gout: Is this really an advance? Colchicine s use in acute gout dates back decades Dates back before the establishment of the FDA and its approval process Thought to inhibit microtubule formation, thereby blocking leukocyte migration into an inflamed joint Classically prescribed only within first 48 hours of symptoms (limits its use) Classically prescribed as repeating doses roughly every 2 hours until the patient develops GI toxicity or begins feeling better This type of therapy generally felt to be dangerous (especially in patients with renal insufficiency), inhumane, and unacceptable Colchicine for Acute Gout FDA approval based upon one study Examined Colcrys in acute gout High dose vs low dose (0.6 mg BID) vs. placebo No comparison to NSAIDs or Prednisone High dose more toxic and no better than low dose FDA approved low dose only No matter how response defined, only about 40% of patients Felt to be more expensive and less effective than NSAIDs or corticosteroids Chronic Gout Serum Urate Lowering Therapies Probenecid Urocosuric Allopurinol (inhibits uric acid formation) Xanthine Oxidase Inhibitor Blocks metabolism of purines to uric acid Effective for both under-excreters and overproducers of uric acid Maximum dose is 300 mg/day, but it is often carefully used at higher doses if needed 12

13 Allopurinol is purine derivative: a dead ringer for hypoxanthine Purine Metabolism Allopurinol competes with Hypoxanthine for xanthine oxidase Allopurinol Toxicities Careful use in patients with renal failure Metabolites are renally cleared hypersensitivity reactions are more common in patients with renal insufficiency Purine-associated hypersensitivity syndrome is DIFFERENT from allergic rash Systemic and sometimes life threatening illness Fever, Steven s-johnson/ten, hepatitis, marrow suppression, nephritis What to do with a More Challenging Case? You are seeing a 56 year old male with long standing diabetes, hypertension, chronic renal insufficiency, and destructive tophaceous gout. In the past few years, his tophi have grown larger, and he suffers from chronic, painful, polyarticular inflammatory arthritis. 13

14 He has chronic swelling, synovitis, and deformities reminiscent of rheumatoid arthritis Numerous tophi scattered on arms, legs, and ears Serum creatinine is 1.8 Uric Acid 10.2 Gout: Findings Management of Chronic Gout in a Challenging Patient Because of his elevated creatinine, you decide to start allopurinol therapy carefully, by beginning with 100 mg QoD, however, the patient develops a fever, rash, and elevated LFTs thought secondary to allopurinol hypersensitivity. Now What?? Febuxostat (FDA approved 2009) First treatment in 40 years in chronic management of gout Fubuxostat is Not a Purine NON-PURINE inhibitor of xanthine oxidase Theoretically safe to use in patients with allopurinol reactions Been studied in patients with mild renal insufficiency Dosed at 40-80mg/once daily 14

15 Purine Metabolism Comparison of Febuxostat to Allopurinol Becker et al. NEJM mg and 120 mg of febuxostat superior to allopurinol 300mg/day Percent of patients achieving uric acid <6 Greater reduction in serum uric acid levels Used in patients with mild-moderate renal insufficiency (SCr <1.5 in this study) Safe for patients with allopurinol reactions Similar reduction in number of gout flares for both agents Becker et al. NEJM 2005 Febuxostat: Summary More potent than 300 mg/day allopurinol (but many patients can tolerate higher doses of allopurinol) As it is not a purine: Appropriate for patients with allopurinol hypersensitivity Can be used safely in patients with mild renal insufficiency (unlike allopurinol) 15

16 Febuxostat: Summary Cannot be used concomitantly with purine based medicines that are metabolized by xanthine oxidase (leads to toxic levels of 6MP, for example) Severe Tophaceous Gout: Use should be reserved for those not controlled by or who have a contraindication to maximal allopurinol therapy Lifetime of standard uric acid lowering treatment won t eliminate these tophi What if.. You could convert relatively insoluble uric acid to a more soluble and excretable metabolite? You could achieve a sustained reduction in uric acid levels below 5? You were a pig? (Pigs don t get gout) You could reverse-engineer evolution? Uricase Enzyme that converts insoluble uric acid to more soluble metabolite allantoin Most of animal kingdom (& many mammals) posses uricase, but not humans have lost gene function Rasburicase: a drug derived from aspergillis used to treat tumor lysis syndrome in pediatric leukemia Rasburicase is extremely immunogenic, which limits its half life and use in chronic diseases 16

17 Pegloticase (FDA approval Sept. 2010) Mammalian uricase Uric Acid Purine Metabolism Urinary Excretion Pegylated Increases half life Reduces immunogenicity Administered by IV infusion every 2 weeks Allantoin Efficacy of Pegloticase Sundy et al. A&R 2008 Efficacy of Pegloticase Phase 2 (12 week) open label dosing trial 41 patients Phase 2 randomized open label dose ranging study 41 patients with serum urate >8 Intolerance or inadequate response to standard urate lowering therapy (UA>6) for at least 3 months Plus one of the following: At least one tophus At least one flare in last 6 months Chronic gouty arthropathy 17

18 Case Report: Visible Results Baraf et al. A&R 2008 Pegloticase: Not holy grail Adverse evets: Infusion reactions (not human, even with PEG) Anaphylaxis 80% patients had gout flares despite prophylaxis Contraindicated in G6PD deficient patients May exacerbate CHF Doesn t work in everybody Many also develop tolerance or become immunized to the medication (increased rate of reactions and diminished efficacy) Pegloticase: Summary Effective agent for acute lowering and chronic reduction in serum uric acid levels Serum uric acid levels are low enough in some patients to promote tophus resorption Medication is expensive, immunogenic, and associated with adverse events Refer these patients with severe tophaceous gout to rheumatologists!! 18