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Current Challenge
February 22, 2012
38 year old male presents to your Rheumatology clinic for evaluation. His current complaints include ulcerations of his tongue, palate, buccal mucosa, posterior Pharynx, Peri-rectal sores/ulcers, joint pain and skin lesions that were biopsy proven e. nodosum type lesions. He was diagnosed with Behcet’s and started on colchicine 0.6mg twice per day, this did not provide significant relief so 2 months later, he was started on Prednisone 30 mg per day and azathioprine 150/d. He improved, but recurrent mucosal and skin lesions developed each time steroids were lowered to less than 15 mg per day. He would like to know what other options he has so he can “get off steroids.”
Response B. The treatment of Behcet’s disease is complex and generally guided by which organ systems are involved. In this case it is largely mucocutaneous. The patient has been treated with standard escalating therapy which has been demonstrated to be effective here including colchicine, glucocorticoids and anti metabolites(1). The next logical step her is a trial of a TNF inhibitor(2). Other options may include the use of IFN alpha, cyclosporine or thalidomide.
References
Alpsoy E. Behçet's disease: treatment of mucocutaneous lesions. Clin Exp Rheumatol. 2005;23(4):532.
Sfikakis PP, Markomichelakis N, Alpsoy E, Assaad-Khalil S, Bodaghi B, Gul A, Ohno S, Pipitone N, Schirmer M, Stanford M, Wechsler B, Zouboulis C, Kaklamanis P, Yazici H
Anti-TNF therapy in the management of Behcet's disease--review and basis for recommendations. Rheumatology (Oxford). 2007;46(5):736.
36 year old female presents to her primary care MD for routine physical. On exam the nurse could not obtain a blood pressure in her left arm. Blood pressure in the right arm was 100/60. In further ROS, she states she is “having a hard time blow drying her hair with my left arm” and new onset low-grade fever, fatigue and intermittent jaw pain.
Response: D. This is a common presentation for large vessel vascular disease. There are hints that the condition may be inflammatory in the way of systemic symptoms (fever, fatigue). A careful exam in search of other silent lesions including a search for bruits and 4 extremity BP determinations is logical. Screening lab exams including acute phase reactants can be helpful but are not highly sensitive in focal disease. Lastly a high quality vascular imaging study is essential.
A 50 year old male with GPA since 2008 is having his routine monthly labs done to monitor his methotrexate. He is off steroids and has not has a flare up since his initial diagnosis in 2008, for which he received cyclophosphamide for 6 months with high dose steroids that were tapered off over 6 months. His labs look good with the exception of a mildly elevated sedimentation rate, 45mm/h (normal 0-20) and new 2+ blood in his urine. You call him over the phone and he reports his home urine dipsticks have showed blood for the past 2 days. He also states he has some joint pain but states “I must just be getting old.”
Response: C. have him immediately come to the clinic for an evaluation of his urine sediment
While several possibilities exist for the etiology of the hematuria and abnormal labs the "must rule out" here is a major flare of his vasculitis. Determining whether he is experiencing a rapid rise of creatinine and or the development of RBC casts in his urine (both of which would signify a major flare) is critically important. If this does not appear to be the case other possibilities can be pursued including a work up of a bladder source with possible neoplasia.
41 year old male with GPA since 2000 presents to your clinic for follow up. He has had multiple relapses almost all of which have been severe enough to require cyclophosphamide induction. His course was complicated by avascular necrosis of the hips following his initial induction but he has overall done well with very little disease or treatment related damage. In 2006 he elected to stop all of his treatment. He remained in remission off all medications for about 3 years.
In 1/09 he had a severe relapse involving his skin, joint, kidney with normal renal function. Treatment options were discussed and we elected to return to cyclophosphamide. He achieved remission and we attempted to transition to mycophenolate mofetil. He did not tolerated this and so azathrioprine was given and the patient had a severe allergic reaction to it. Methotrexate was attempted but he developed leukopenia on it and it was stopped. One month later, the patient again had a severe flare, this flare was treated with Rituximab, which was tolerated well, and 2 months later, remission was achieved and the patient was weaned to 5 mg per day of Prednisone.
At this point there is no right or wrong answer among these possibilities. Some data suggests the return of B cells and ANCA are helpful in gauging therapy ( Specks et al, ACR 2010 abstract 680) while others have demonstrated major flares in the absence of B cells (Molloy et al ACR. Arthritis Rheum. Supple. 2007; 56). Finally data from the RAVE trial suggests that nearly 40% of patients may attain complete remission off all medications status post rituximab for up to 18 months (Specks, et al. Clin Exp Immunol. 2011;164(Suppl1):65). Clear predictors of this are lacking for now, though relapse appears more common with GPA, +PR3 and relapsing cases (Stone, et al. ACR 2011. Abstract 2432).
40 year old male comes to your vaculitis clinic with complains of “terrible eye pain”, migratory arthalgias and increased nasal bleeding. He has known GPA since 1996 which has affected his joints, sinuses, nose (crusting, bleeding and saddle-nose deformity), kidneys (hematuria with normal creatinine) and eyes (conjunctivitis), he is C ANCA-PR-3 + at time of diagnosis. Although he was initially treated with high dose steroids and cyclophosphamide in 1996, he has been in remission on prednisone 5mg/d in combination with methotrexate 25 mg/wk SQ. When you examine him you note there is proptosis of the right orbit and diplopia with lateral gaze. An orbital CT scan is done, it shows Right orbital mass, new since 1997 that measures 2.2 x 1.9 cm.
A: d. Start Prednisone 60mg/d and Rituxan 1 gm, repeat in 2 weeks
This is a difficult problem and one that is highly morbid. By definition it is a serious flare. Orbital disease can be highly refractory to therapy. Results are mixed as to response with rituximab but there are anecdotes favoring this approach (especially after failing cyclophosphamide). Unfortunately, orbital disease tends to represent a more granulomatous type of reaction (versus pure vasculitis) and these patients may not respond as well. Because of the severe eye pain an induction of methylprednisolone pulse (1 gr per day for 1 -3 days) may also be helpful.
Reference:
EULAR 2011 Abstract
[OP0055] RRETROSPECTIVE STUDY OF RITUXIMAB (RTX) IN REFRACTORY GRANULOMATOSIS WITH POLYANGIITIS (WEGENER'S) (WG): COMPARISON OF TREATMENT RESPONSE IN VASCULITIC VERSUS GRANULOMATOUS MANIFESTATIONS. J.U. Holle, C. Mueller, W.L. Gross, E. Csernok, E. Reinhold-Keller Dept. of Rheumatology, University Hospital Schleswig-Holstein, Campus Luebeck, Germany
38 year old female is evaluated by her primary care MD and found to have an asymptomatic aortic insufficiency murmur. She is referred to a cardiology who then finds thickening of the ascending and descending aorta "c/w with vasculitis".
Labs show a sedimentation rate of 82, C - reactive protein of 7.8 and platelet count of 584. Her history is only remarkable for Grave’s disease, for which she had RAI treatment. Further work up reveals addition stenosis of the bilateral renal arteries, right sub-clavian and left carotid. Her infection w/u is negative. You diagnosis her with Takayasu’s arteritis. She has heard “horror stories” about prednisone and does not want to take it. What are the treatment options you discuss?
Unfortunately glucocorticoids are still the mainstay of therapy of this case of clear and active Takayasu arteritis. The initial dose is generally 45-60mg per day and we may go on the lower side because of our patients concern. A second agent is advantageous to lowering the total burden of steroids that may be needed and methotrexate is the traditional drug of 1st choice. Emerging data on the use of anti-TNF agents is encouraging but should likely be reserved
Reference:
Liang P, Hoffman GS. Advances in the medical and surgical treatment of Takayasu arteritis. Curr Opin Rheumatol. 2005 Jan;17(1):16-24. Review.
Maksimowicz-McKinnon K, Clark TM, Hoffman GS. Limitations of therapy and a guarded prognosis in an American cohort of Takayasu arteritis patients. Arthritis Rheum. 2007 Mar;56(3):1000-1009 Review.
A 50 year old male presents to the hospital with rapid progressive kidney failure. On admission his creatinine is 5.6, he has new onset hematuria with adbundant RBC casts and is C ANCA/PR-3 +. Upon further evaluation, he notes recurrent episodes of nasal bleeding, sinusitis and a cough. His imaging studies show bilateral pulmonary infiltrates and mucosal thickening of his maxillary sinuses. He is diagnosed with GPA and given steroids (1mg/kg) and Rituximab therapy (1 gm repeated 2 weeks later) + started on dialysis. After 3 months he is doing well and down to Prednisone 5mg/d but still has a creatinine of 5.0. Would renal transplant be an option for a GPA patient like this?
Transplant is a good option for this patient. Based on the 2011 data present at Chapel Hill by
Relapse rate post transplant was low. However, there was a significantly higher relapse rate in those that were ANCA positive. Kidney transplant is safe and effective option for treating ESRD secondary to AAV, relapses are rare with current immunosuppressive regimens.
Reference:
Shen J, et al. Clin Transplant 2010 DOI: 10.1111/j.1399-0012.2010.01248
GÖçerog˘lu, A et al DUTRAVAS study group Chapel Hill 2011
Geetha D, et al. Clin Exp Immunol 2011;164 (suppl 1):56
30 year old female has known GPA which has involved his nose, sinuses, ears, joint, kidneys (peak creatinine of 2.0) and his was C ANCA/PR-3 positive. He initially received induction therapy of cyclophosphamide for 4 months and steroids. He achieved remission and has been on azathioprine 150mg per day and is off steroids since 2009. Today he is having arthalgia’s, nasal bleeding and new bilateral pulmonary infiltrates on CT. His bronchscopy showed + hemosiderin laden macrophages and no infection, what is a reasonable course of action?
While both B and D are reasonable options. Option B may have the least potential for adverse effects due to cumulative cyclophosphamide dosing in this young female. Based on the 2010 data published in the New England Journal of Medicine (1), disease remission was reported in 63.6% of the rituximab group and 53.1% of the cyclophosphamide group. A reduction in disease activity, measured by a score of 0 on the Birmingham Vasculitis Activity Score for Wegener's granulomatosis, and tapering of prednisone to less than 10 mg/day was observed in 70.7% of the rituximab group and 62.2% of the cyclophosphamide group. The rate of protocol-defined adverse events was similar between groups (0.06% for rituximab and 0.08% for cyclophosphamide), with no difference in rate of infection. Fewer patients treated with rituximab experienced 1 or more adverse event(s), compared with cyclophosphamide (19.2% vs 32.7; P = .03)
Reference:
Stone J H, et al. N. Engl J med 2010; 363:221-32
Specks U, et al. Clin Exp Immunol 2011;164 (suppl 1):65
27 year old woman comes to the office with malaise and rash of 4 weeks duration, She was previously healthy and takes no medications. The rash is described as erythematous and palpable and non-blanching (i.e. palpable purpura). It is located predominately on the lower extremities. She has no other symptoms and her exam is otherwise normal.
This patient has classic inflammatory purpura and is very likely to have leukocytoclastic vasculits on skin biopsy. It should be noted however that all non-blanching erythematous palpable lesions represent LCV. Insect bites, secondary trauma to skin, Kapsoi sarcoma just to name a few remind us of the value of a skin biopsy in the approriate setting. The leading casues of LCV are true hypersensitivity vasculitis secondary to an exogenous antigen such as a drug, protein or toxin, HSP in young person, virtually any connective tissue disease, cryoglobulinemia secondary to HCV or other etiology and systemic vasculitis with cutaneous involvement. Malignancy is a rare cause of LCV but must be considered in the differential diagnosis when the 'usual suspects' are not present. In this case a closer evaluation reveale an active urinary sediment with RBC casts suggesting a systemic form of vasulitis or connective tissue disease susch as SLE. An ANCA test was strongly positive for PR3 in a cANCA pattern. The patient had granulomatosis and polyangiitis (Wegener's).
Reference:
Stone, John H. (Ed.). A Clinician’s Pearls and Myths in Rheumatology. 2nd Printing. Springer-Verlag . 2010, XVI: Chap 24.10 and 25.
A 38 year old woman comes in for 12 months of not feeling well. She has diffuse aches and pains mostly in the muscles and fatigue. She has no fever, rash, weight loss. She is referred to you the rheumatologist because she has the following laboratory test.
ANCA testing is a powerful tool but must be performed to international standards and must be interpreted with caution. In the setting of AAV only ANCA tests demonstrating both + IFA and antigen specific assays fro PR3 or MPO are "diagnostic" with test specificty exceeding 95-99%. ANA reactivity s the most common cause of a pANCA pattern by IFA but will be negative for MPO or PR3
References:
Calabrese LH, Molloy ES, Duna G. Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. In: Firestein GS, Budd RC, Harris ED Jr., McInnes IB, Ruddy S, eds. Kelley's Textbook of Rheumatology. 8th ed. Philadelphia, Pa: Saunders Elsevier; 2008: Chap 82.
Antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis.Finkielman JD, Merkel PA, Schroeder D, Hoffman GS, Spiera R, St Clair EW, Davis JC Jr, McCune WJ, Lears AK, Ytterberg SR, Hummel AM, Viss MA, Peikert T, Stone JH, Specks U; WGET Research Group.
October 5th, 2011
A 45 year old woman comes in with a 12 week history of numbness and tingling of the right lower extremity. She has been well but has a history of allergic rhinitis and asthma over the past 8 years. On exam she has a sensory defect in a stocking distribution of the right lower leg and weakness of dorsiflexion of the right foot. Her CBC reveals a WBC of 12,000 with 18% eosinophils. Her ESR is 38 mm hr. CMP and UA are normal A CXR is negative.
This patient should be approached as an FUO type of problem. While not technically an FUO because he has not had an exhaustive work up it is a similar problem. The chronicity would suggest a systemic inflammatory inflammatory disease of infectious, neoplastic or autoimmune origin. Among autoimmune or inflammatory disease states a form of systemic vasculitis would be high on the list as well as other connective tissue diseases
Reference:
Inflammatory Diseases of Blood Vessels edited by Gary S. Hoffman and Cornelia M. Weyand: 2002, Chapter 17. General Approach to the Diagnosis of Vasculitis Brian F. Mandell p 239-255.
September 23rd, 2011
A 58 year old man comes in with a 5 month history of malaise arthralgia, intermittent fever to 101F and weight loss (1o lbs). He had been previously healthy and on no medications. His exam is unremarkable except some symmetric joint tenderness in the wrists and ankles without synovitis. Initial laboratory tests revealed a mild anemia of 12.2grms Hb a normal metabolic and renal profile and UA. An ESR is 48mm hr.
In my opinion 1, 2 & 3 are appropriate. There is a strong likelihood of this representing Churg Strauss disease. Peripheral neuropathy is found in 75 % of patients and this will likely represent a mononeuritis like pattern. In small vessel vasculitis a normal chest x-ray is not sensitive for all lung based disease and a CT may further define and detect disease in a significant percentage of patients. ANCA can be helpful if positive but less than 40% of Churg Strauss is ANCA positive. I would not do a sural nerve biopsy at this juncture as the procedure is invasive and morbid. I would reserve it only if the overall picture remains unclear after the initial evaluation.
References:
Churg Strauss syndrome: evidence for disease subtypes? Pagnoux C, Guillevin L. Curr Opin Rheumatol. 2010 Jan;22(1):21-8. Review
Clinical Manifestations and treatment of Churg-Strauss syndrome Baldini C, Talarico R, Della Rossa A, Bombardieri S.Rheum Dis Clin North Am. 2010 Aug;36(3):527-43. 2010 Jun 20
