Marked Cryoglobulinemia in Rheumatoid Arthritis

Marked Cryoglobulinemia in Rheumatoid Arthritis Marina N Magrey April 2008 History • 55 yr Caucasian male - RA and COPD – rash – joint pain & swelling • RA 3 yrs - swollen elbows, wrists, MCPs, PIPs, morning stiffness • • • • • Laboratory: RF 110 (high) ANA - 1:1280 CCP-170 anti-DNA, ENA negative History • Treatment- Celecoxib, hydroxycholorquine, leflunomide and Etanercept – 3 yrs • 4 months – pneumonia - meds discontinued • 6 wk- ↑ swelling, pain - hands, wrists • rash - legs, abdomen & upper arms. History • Diagnosed elsewhere- Henoch-Schonlein purpura • Prednisone 40mg/d • No improvement • Transferred to our hospital Physical Exam • Alert , no acute distress, afebrile • Mild tachycardia • Swelling – wrists and MCPs Physical Exam Laboratory Evaluation • • • • • • • CRP- 8.7mg/dl ESR- 21 mm/hr WBC- 7.42 K/µL Hg- 11.1g/dl Platelet - 586 K/ µL C4 < 2 mg/dl C3 = 105 mg/dl • • • • • • • RF- 2844 IU/ml CCP > 250 units ANA- 1:640 – ENA neg SSA/SSB- neg Cryoglobulins- 2933 µg/ml UA- neg Anti-DNA- neg Type 2 (Mixed Cryoglobulinemia) • • • Monoclonal IgM kappa Polyclonal IgG Skin BiopsyLeukocytoclastic vasculitis What are the Possibilities • Hepatitis C associated mixed cryoglobulinemia • Non- HC associated mixed cryoglobulinemia • Mixed cryoglobulinemia & Hepatitis C (60- 100 %)1,2 1.Ferri et al; Seminars in Arthritis and Rheumatism 2004; 33,355-374 2. Ferri et al; Lupus (1998) 7,275-279 Non HCV- related mixed cryoglobulinemia • • • • • • 195 patients- MC 31/195 (15.95 %)- HCV (–) 18/31 (58%)- CTD 9/31 (29%) – essential MC 2/31 (6%)- malignancy 2/31 (6%)- infections Mascia et al; Digestive and Liver Disease (2007) 39, s61-s64 Type II mixed cryoglobulinemia • Of CTD - Sjogren’s syndrome- (70%) • Of malignancies - B- cell lymphomas – (80%) Further Testing of our patient • Hep C antibody & RNA, HepBs antigen and antibody , HIV were all negative • CT – chest & abdomen - No significant lymphadenopathy Further Testing • ? Monoclonal Protein found in the blood “Possible M protein (matching poorly defined regions – restricted mobility in IgA and kappa. Favor monoclonal gammopathy but an atypical polyclonal response pattern or oligoclonal expansion of the type that may be seen in chronic inflammatory conditions cannot be entirely excluded”. • Monoclonal Protein in urine - Free kappa light chain • Skeletal survey negative Diagnostic possibilities • Lymphoproliferative malignancy with cryoglobulinemic vasculitis vs. • Rheumatoid vasculitis • Pt refused bone marrow biopsy Cryoglobulinemia in RA • Not much in literature • Cryoglobulins – described in sera and synovial fluid • Cryoglobulinemia – extra-articular manifestations1-2 • Protein concentration low: 0.15- 0.66 mg/ml • No Hepatitis C testing available then 1- Erhardt et al; Clin.exp. Immunology (1979) 38,405-413 2- Weisman et al; The journal of Clinical Investigation (1975) 725-739 3- Frieri M; Immunologic Complications in Rheumatoid Arthritis. "Emergencies in Rheumatoid Arthritis," 73-106 Treatment for Type II mixed cryoglobulinemia • Best treatment still to be defined • Type II MC – systemic vasculitis – immune complexes- proliferation of RF positive B-cell clones – cryoglobulins • Strong Rationale to use Rituximab - chimeric monoclonal antibody against CD-20 antigentargeting B cells Efficacy and Safety of Rituximab in Type II MC • 15 pts- 12/15- HCV related. • Dose- 375mg/m² weekly x 4weeks • Medium to low dose steroids allowed. Zaja et al; Blood: vol 10, May-2003 Efficacy of Rituximab • Efficacy evaluated in 6 mos • Improvement» » arthralgia peripheral neuropathy low grade fever • Decreased RF and cryoglobulin • Increased C4 Treatment of our patient • Rituximab 1000 mg x 2: • • • • • • Improvement - rash, & joint swelling Prednisone tapered -10mg/d ESR-42 mm/hr RF- 2844 C4< 1mg/dl Cryoglobulins- not detected ?error Limitations • Refused Bone marrow biopsy • Hepatitis C antibody and RNA negative but cryoprecipitate not checked for Hepatitis C • Lack of follow up Marked Cryoglobulinemia in RA • Can cryoglobulinemia of this magnitude be associated with RA without underlying HCV infection or lymphoproliferative malignancy ? Plausible Explanations • Certain patients with RA may have a unique immunogenetic profile that predisposes them to have an amplified autoimmune response • Expansion of CD5+ B cells 1-3 • Persistent B cell stimulation by auto antigens and excess levels of BAFF 4 1. Loza et al: Rheumatology 1999;38:325-328 2. Ferraccioli et al : Autoimmunity reviews 2007;109-113 3. Nakiri et al: Clinical Rheumatology 2007; 1721-1723 4. Hansen et al: Nature and Clinical Practice Rheumatology 2007, 3; 561-569 Looking forward to Your Comments and Suggestions