Successful treatment with intraarticular infliximab for resistant knee monarthritis in a patient with spondylarthropathyA role for scintigraphy with 99mTc-infliximab.код для вставкиСкачать
ARTHRITIS & RHEUMATISM Vol. 52, No. 4, April 2005, pp 1224–1226 DOI 10.1002/art.20979 © 2005, American College of Rheumatology Successful Treatment With Intraarticular Infliximab for Resistant Knee Monarthritis in a Patient With Spondylarthropathy A Role for Scintigraphy With 99m Tc-Infliximab Fabrizio Conti, Roberta Priori, Maria Sole Chimenti, Giulio Coari, Alessio Annovazzi, Guido Valesini, and Alberto Signore Positive experiences with intraarticular infliximab have been reported in patients with rheumatoid arthritis, ankylosing spondylitis, and Behçet’s disease. We used intraarticular infliximab to treat resistant knee monarthritis in a patient with spondylarthropathy. Clinical and laboratory improvement was associated with improvement in scintigraphic findings. This approach is less expensive than intravenous administration of infliximab. We suggest that selection of candidates for this innovative therapy should be guided by anti–tumor necrosis factor ␣ scintigraphy. riences with intraarticular infliximab in patients with RA, AS, and Behçet’s disease have been reported (8–11). CASE REPORT The patient, a 34-year-old HLA–B27–positive white man, had undifferentiated spondylarthropathy. His clinical history began 2 years previously, with left knee arthritis, buttock pain, inflammatory spinal pain, and recurrent right iritis. During these years he was treated with oral steroids and sulfasalazine and experienced global improvement except for the left knee arthritis, with relapses occurring more and more frequently. At the time of admission to our rheumatology division in December 2003, the patient was receiving sulfasalazine 4 gm daily and rofecoxib 50 mg daily. He presented with arthritis of the left knee and back pain at night. He had experienced a flare of uveitis during the last 2 months and was treated with local and systemic steroids. Laboratory findings included an erythrocyte sedimentation rate (ESR) of 20 mm/hour and a C-reactive protein (CRP) level of 9 mg/dl. Ultrasonography of the involved knee showed synovial thickening, proliferation, a large effusion, and power Doppler positivity (Figure 1A). An arthrocentesis was performed, and 50 ml of inflamed sterile synovial fluid was extracted. Intramuscular methotrexate, 15 mg weekly, was added to the regimen of sulfasalazine and rofecoxib. After 3 months, the patient experienced frank improvement of the spinal pain, and no recurrence of iritis was observed. However, arthritis in the left knee persisted in spite of a 40-mg intraarticular injection of methylprednisolone acetate Tumor necrosis factor ␣ (TNF␣) plays a central role in the pathogenesis of synovial inflammation, and the levels of TNF␣ are increased in inflamed joints (1,2). During the past few years, intravenous infliximab, a chimeric monoclonal antibody against TNF␣, has become a well-established treatment for rheumatoid arthritis (RA) (3) as well as other inflammatory polyarthritides such as psoriatic arthritis (4), ankylosing spondylitis (AS) (5), undifferentiated spondylarthropathies (6), and spondylarthropathies associated with Crohn’s disease (7). More recently, some positive expeFabrizio Conti, MD, Roberta Priori, MD, Maria Sole Chimenti, MD, Giulio Coari, MD, Alessio Annovazzi, MD, Guido Valesini, MD, Alberto Signore, MD: Università degli Studi di Roma “La Sapienza,” Rome, Italy. Drs. Conti and Priori contributed equally to this work. Address correspondence and reprint requests to Alberto Signore, MD, Medicina Nucleare, Dipartimento Scienze Cliniche, Università degli Studi “La Sapienza,” Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy. E-mail: alberto.signore@ uniroma1.it. Submitted for publication October 26, 2004; accepted in revised form January 14, 2005. 1224 INTRAARTICULAR INFLIXIMAB IN SpA 1225 Figure 1. Ultrasonography of the affected knee before (A) and after (B) intraarticular injection of infliximab. Intraarticular infliximab administration resulted in a dramatic reduction in thickness and amelioration of proliferation in the synovial membrane, disappearance of the initial large effusion, and negative power Doppler results. (the degree of swelling and tenderness was graded as severe, and the pain score on a 100-cm visual analog scale [VAS] was 52). Use of an intraarticular TNF␣ antagonist was proposed. In order to assess the degree of TNF␣ expression in the affected knee, we performed scintigraphy with 99m Tc-infliximab. Infliximab was radiolabeled using a direct labeling method, as previously described (12). After in vivo injection of 15 mCi of 99mTc-infliximab, planar images of the knees were acquired at 6 and 24 hours. Scintigraphy showed an intense accumulation of the radiopharmaceutical agent in the left knee, indicating high levels of intralesional TNF␣ (Figure 2A). Negative results of tuberculin skin testing and normal results of chest radiography were also obtained. After the patient gave informed consent, 80 ml of synovial fluid was removed, and 100 mg of infliximab mixed with 10 ml of sterile water, according to the manufacturer’s Figure 2. Scintigraphy with 99mTc-infliximab before (A) and 4 months after (B) intraarticular administration of infliximab. Strong uptake of 99mTc-infliximab is detectable in the left knee in the scintigraph obtained before therapy (A), while no uptake can be observed in the second scan (B), confirming the complete remission. 1226 CONTI ET AL instructions, was injected into the left knee as a single dose. The treatment was well tolerated, and no adverse reaction occurred locally or systemically. The patient was reevaluated after 7 and 15 days, then monthly for 4 months, and then bimonthly, for a total of 8 months of followup. Complete remission of knee arthritis was observed each time (VAS score for pain ⫽ 0; no swelling or tenderness). Because of the dramatic improvement that was observed, rofecoxib was stopped 10 days after administration of infliximab. After 4 months of followup, both the ESR and the CRP level were normal, and ultrasonography revealed a reduction in thickness and amelioration of proliferation in the synovial membrane; results of power Doppler imaging were negative (Figure 1B). At that time, a new scintigraph with 99mTc-infliximab showed no accumulation of the radiopharmaceutical agent in the knees, indicating the absence of detectable levels of TNF␣ (Figure 2B) and confirming the efficacy of intraarticular infliximab treatment in the previously affected knee. After an additional 4 months, the patient is still asymptomatic, with no signs of active knee arthritis. DISCUSSION Intraarticular infliximab proved to be effective in this case of refractory knee synovitis in a patient with undifferentiated spondylarthropathy. In a previous report, this new therapeutic approach failed in a group of 6 patients with different types of arthritis, including 4 cases of spondylarthropathy (13). Our patient was treated with both sulfasalazine and methotrexate for more than 3 months, a treatment that was able to improve all of the patient’s clinical signs and symptoms (buttock pain, spinal pain, and recurrent right iritis) except the left knee arthritis. Knee synovitis that was unresponsive to systemic therapy did not resolve after the patient received an intraarticular steroid injection. The demonstration of high levels of TNF␣ in only the affected knee, using radiolabeled anti-TNF␣ scintigraphy, prompted us to use intraarticular infliximab in this patient. The impressive and sustained clinical response demonstrated the central role of TNF␣ in the pathogenesis of this kind of monarthritis. The clinical and laboratory improvement was associated with improvement in scintigraphy findings, which showed the absence of detectable levels of TNF␣ in the affected knee. The good clinical outcome was confirmed by power Doppler sonography. This report, together with several previous re- ports (8–11), supports the use of intraarticular infliximab in selected cases of inflammatory monarthritis resistant to traditional therapeutic approaches. In this case, a single 100-mg intraarticular injection of infliximab led to a prolonged clinical response at a dramatically lower cost than that associated with the intravenous approach, and avoiding further hospitalization. We suggest that the selection of patients who are candidates for this innovative intraarticular therapy should be guided by antiTNF␣ scintigraphy, although large placebo-controlled studies are required to better define the diagnostic and prognostic criteria. REFERENCES 1. Neidel J, Schulze M, Lindschau J. Association between degree of bone-erosion and synovial fluid-levels of tumor necrosis factor ␣ in the knee-joints of patients with rheumatoid arthritis. Inflamm Res 1995;44:217–21. 2. Partsch G, Wagner E, Leeb BF, Dunky A, Steiner G, Smolen JS. Upregulation of cytokine receptors sTNF-R55, sTNF-R75, and sIL-2R in psoriatic arthritis synovial fluid. J Rheumatol 1998;25: 105–10. 3. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al. Infliximab (chimeric anti-TNF␣ monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomized phase III trial. Lancet 1999;354: 1932–9. 4. Gladman DD. Effectiveness of psoriatic arthritis therapies. Semin Arthritis Rheum 2003;33:29–37. 5. Braun J, Brandt J, Listing J, Zink A, Alten R, Golden W, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002;359:1187–93. 6. Brandt J, Haibel H, Reddig J, Sieper J, Braun J. Successful short term treatment of severe undifferentiated spondyloarthropathy with the anti-tumor necrosis factor-␣ monoclonal antibody infliximab. J Rheumatol 2002;29:118–22. 7. Van den Bosch F, Kruithof E, de Vos M, de Keyser F, Mielants H. Crohn’s disease associated with spondyloarthropathy: effect of TNF-␣ blockade with infliximab on articular symptoms. Lancet 2000;356:1821–2. 8. Nikas NS, Temekonidis TI, Zikou AK, Argyropoulou MI, Efremidis S, Drosos AA. Treatment of resistant rheumatoid arthritis by intra-articular infliximab injections: a pilot study. Ann Rheum Dis 2004;63:102–3. 9. Dreher R, Flaig W, Leitzeke D. Treatment of rheumatoid arthritis by intra-articular injections with TNF ␣ blockers [abstract]. Arthritis Rheum 2001;44 Suppl 9:S42. 10. Kellner H, Kroetz M, Schattenkirchner M, Kellner W. Successful therapy of sacroileitis in AS patients by intraarticular injection of infliximab [abstract]. Arthritis Rheum 2002;46 Suppl 9:S431. 11. Andonopoulos AP, Meimaris N, Daossis D, Bounas A, Yiannopoulos G. Intraarticular anti-tumor necrosis factor ␣ antibody in recalcitrant arthritis of Behcet’s disease. Clin Exp Rheumatol 2003;21 Suppl 30:S57–8. 12. Annovazzi A, D’Alessandria C, Caprilli R, Viscido A, Corsetti F, Parisella MG, et al. Radiolabelling of a monoclonal anti-TNF␣ antibody with 99mTc: in vitro studies [abstract]. Q J Nucl Med 2002;46 Suppl 1:27. 13. Bokarewa M, Tarkowski A. Local infusion of infliximab for the treatment of acute joint inflammation. Ann Rheum Dis 2003;62: 783–4.