JCR: Journal of Clinical Rheumatology:
Drug-Induced Lupus After Treatment With Infliximab in Rheumatoid Arthritis
Benucci, Maurizio MD*; Gobbi, Francesca Li MD*; Fossi, Fiammetta MD*; Manfredi, Mariangela BD†; Del Rosso, Angela MD‡
From the Sections of *Rheumatology and †Immunology, Nuovo Ospedale di S. Giovanni di Dio ASL 10, Florence, Italy; and the ‡Department of Medicine, Section of Rheumatology, University of Florence, Florence, Italy.
Reprints: Maurizio Benucci, MD, Section of Rheumatology, Nuovo Ospedale S. Giovanni di Dio, Via di Torregalli 3 50143, Florence, Italy. E-mail: email@example.com or firstname.lastname@example.org.
We report a case of a 45-year-old man with an 8-month history of rheumatoid arthritis, who was treated with hydroxychloroquine 400 mg per day and 15 mg intramuscular methotrexate per week without reaching a good control of the disease. The patient was successfully treated with 3 mg/kg infliximab for 20 weeks. Before the last infusion, drug-induced lupus (DIL) was diagnosed based on the clinical features of fever > 37.5°C, recurrence of active synovitis, myalgia, erythematosus rash, pericardial and pleural effusion, and of some laboratory findings (antinuclear antibodies 1:160 and anti double-strand DNA positive by DNA recombinant plasmid assay dsDNA). After infliximab discontinuation and the beginning of therapy with methylprednisolone, lupus symptoms resolved within 6 weeks. A new rheumatoid arthritis flare, occurring after 8 weeks, was controlled by methotrexate plus leflunomide. We also review the development of antinuclear and antidouble-strand DNA antibodies and drug-induced lupus in patients treated with anti-TNFα agents (infliximab, etanercept, and adalimumab).
Many different drugs such as procainamide, hydralazine, sulfasalazine, penicillamine, and interferon have been implicated in the induction of drug-induced lupus as well as the induction of lupus-related autoantibodies without clinical symptoms. Since anti-TNFα treatments were introduced in the therapy for rheumatoid arthritis (RA), some cases of patients with drug-induced lupus during clinical trials with infliximab treatment of RA and Crohn disease were reported.1,2
We report a case of a 45-year-old man with an 8-month history of refractory RA, who developed drug-induced lupus (by clinical features and autoantibody assessment) after 20 weeks of treatment with the anti-TNFα agent infliximab.
In May 2002, a 45-year-old man presented at the outpatient clinic of the Section of Rheumatology of Nuovo Ospedale S. Giovanni di Dio (Florence) with polyarthritis at the wrists, metacarpophalangeal joints, knees, and ankles, and morning stiffness lasting 2 hours. RA was diagnosed, and therapy with 8 mg methylprednisolone per day, 400 mg hydroxychloroquine per day, and 15 mg intramuscular methotrexate per week was started.
On October 16, 2002, the patient was admitted to our inpatient clinic for a relapse of RA. On admission, he had 12 tender joints, 7 swollen joints, the Ritchie Index was 15, erythrocyte sedimentation rate (ESR) was 65 mm/h, C-reactive protein (CRP) was 3.02 mg/dL (normal range, < 0.5 mg/dL), rheumatoid factor was 160 UI/mL, global assessment (GA) with visual analog scale (VAS) was 70, disease activity score (DAS) was 5.27, and DAS 28 was 6.58. Full blood cell count was normal and antinuclear antibodies (ANA), antidouble-stranded DNA (antidsDNA), and antiextractable nuclear antigen (ENA) were negative.
X-rays of the hands and wrists showed 2 marginal erosions at the right ulnar styloid and at the second metacarpophalangeal of the right hand.
After the execution of Mantoux (10 U), which was negative, the patient was started on infusions of 3 mg/kg infliximab on days 0, 15, and 45 and then every 8 weeks. After the third infusion, he presented a significant reduction of disease activity (number of tender joints: 2, number of swollen joints: 2, Ritchie Index: 4, GA with VAS: 30, ESR: 22 mm/h, CRP: 0.5 mg/dL, DAS: 2.64, and DAS 28: 3.77). After the fifth infusion, on April 17, 2003, the patient complained of a week's history of fever (37.5°C), cough, polyarthralgia, and chest pain. Physical examination revealed an erythematosus rash on the face, neck, and forearms and arthritis of the hands and wrists. Chest auscultation revealed a reduction of vesicular breath in the left hemithorax. Echocardiography and chest x-ray showed a pericardial and pleural effusion. Mantoux test was negative.
ESR and CRP were increased (108 mm/h and 2.8 mg/dL, respectively); positivity of ANA (1:160 with homogeneous pattern, by indirect immunofluorescence) and antidsDNA (225 IU/mL, by recombinant plasmid assay; Varelisa ds DNA Antibodies Assay, Pharmacia Diagnostics GMBH) were found (negative < 55 IU/mL); antihistone antibodies (by quantitative enzyme immunoassay Kallestad) were negative. C3 was reduced (85 mg/dL; normal range, 90–180 mg/dL) and C4 was normal; serum creatinine and urinalysis were normal and proteinuria was absent.
A diagnosis of drug-induced lupus was made and 40 mg methylprednisolone per day was started. Infliximab was immediately discontinued. Hydroxychloroquine at a dose of 400 mg per day was maintained. Follow up at 6 weeks showed significant improvement of clinical symptoms and a resolution of pericardial and pleural effusion, negative ANA and antidsDNA, and decreased levels of ESR (36 mm/h) and CRP (1.26 mg/dL). After 8 weeks after a new flare of RA, the patient discontinued hydroxychloroquine and was started on a combination therapy with 10 mg methotrexate per week plus 20 mg leflunomide per day with a good control of symptoms in the follow up until now.
Drug-induced lupus is a difficult clinical entity to be recognized and, although diagnosis is supported by suggested guidelines, specific criteria have not been formally established. In fact, patients often do not fulfill ACR criteria for systemic lupus erythematosus (SLE).3
In the first open-label study, 2 of 20 patients with RA treated with infliximab (monoclonal chimeric antibody against TNFα) developed antibodies to dsDNA, although none of the patients developed any clinical feature of SLE.4 Charles et al demonstrated that the incidence of ANA in a group of 156 patients with RA treated with infliximab rose from 29% pretreatment to 53% posttreatment. AntidsDNA antibodies were detected in 22 of 156 patients (14%), but only 1 patient developed drug-induced lupus, which resolved within 8 weeks of treatment with oral prednisolone. Only this patient had antidsDNA antibodies of IgG, IgA, and IgM classes.5 In the ATTRACT study of 102 weeks, 53% to 68% of patients treated with infliximab developed ANA autoantibodies, but only 7% to 10% became positive for antidsDNA antibodies. One patient developed drug-induced lupus characterized by rash and ANA titer rising from 1:40 at baseline to 1:80 after treatment, associated with low complement levels.6,7 In patients treated with infliximab, the development of antidsDNA has been reported in up to 16% of patients, but clinically relevant drug-induced lupus is extremely rare.2 In placebo-controlled infliximab trials, 5 of 2292 patients receiving infliximab (2 with RA and 3 with Crohn disease: 0.22%) developed drug-induced lupus. Rare cases of drug-induced lupus have also been shown with infliximab in postmarketing reports.8
Information about the effects of etanercept (a soluble TNFα receptor) on autoantibodies is available from controlled trials in RA.9–11 In the 3 studies, the percentage of patients who developed ANA positivity (titer > 1:40) was higher in the groups of patients treated with etanercept (11%), and a similar number of patients treated charged from negative to positive for ANA. The percentage of patients who developed new positivity for antidsDNA was higher when tested by radioimmunoassay (15%) than when tested by crithidia luciliae assay (3%).12 A review of spontaneous reports of the U.S. Food and Drug Administration's Adverse Event Reporting System from November 1998 to February 2002 identified 16 cases of drug-induced lupus in patients receiving etanercept. These 16 cases excluded 2 reports of 4 and 1 patients, respectively, discussed in published reports.13,14 A concomitant therapy with methotrexate does not seem to protect against induction of antidsDNA antibodies and in development of drug-induced lupus.5
In recent reports, a difference in the number of patients positive for anticardiolipin autoantibodies (ACLA) at baseline (17%) and after 3 months (27%) of etanercept therapy was noted.15 A possible correlation with Staphylococcus aureus and Escherichia coli infections was discussed.16 Some papers also showed anti-Smith antibodies and antibodies to histone, but no patients presented neurologic and kidney involvement.17
During adalimumab (monoclonal fully human antibody against TNFα) clinical trials, 12.6% of new positive ANA and 3.9% of antidsDNA autoantibodies but only a case of drug-induced lupus was reported.18,19
The putative mechanisms that may induce the onset of ANA and antidsDNA antibodies in patients treated with anti-TNFα agents are still to be determined. Infliximab binds TNFα on cell surfaces and could produce apoptotic cell death, releasing nucleosomal autoantigens, which induce antidsDNA antibodies in a population of genetically susceptible patients. The notable downregulation of CRP that occurs after infliximab treatment may further potentiate autoimmunity by reducing the clearance of nuclear material by CRP.5 Another important observation is that TNFα could upregulate cellular expression of the adhesion molecule CD44, which has a role in the clearance of apoptotic neutrophil by phagocytes.14 An impaired clearance of apoptotic cells and a reduced leukocyte CD44 have been described in SLE.20
1. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusion of anti tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum
2. Kavanaugh A, Keenan G, De Woody K, et al. Long term follow up of patients treated with Remicade in clinical trials. Arthritis Rheum
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3. Rubin RL. Etiology and mechanisms of drug-induced lupus. Curr Opin Rheumatol
4. Elliott MJ, Maini RN, Feldman M. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum
5. Charles PJ, Smeenk RJT, De Jong J, et al. Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor α: findings in open label and randomized placebo controlled trials. Arthritis Rheum
6. Maini R, St. Clair EW, Breedwel F. Infliximab (chimeric anti-tumor necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet
7. Lipsky P, van der Heijde D, St. Clair E, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis (ATTRACT study). N Engl J Med
8. Ali Y, Shah S. Infliximab induced systemic lupus erythematosus. Ann Intern Med
9. Moreland LW, Schiff MH, Baumgartner SW. Etanercept therapy in rheumatoid arthritis: a randomized controlled trial. Ann Intern Med
10. Weinblatt ME, Kremer JM, Bankhurst AD. A trial of etanercept, a recombinant tumor necrosis factor receptor/Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med
11. Genovese MC, Bathon JM, Martin RW, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum
12. Shakoor N, Michalska M, Harris CA, et al. Drug induced systemic lupus erythematosus associated with etanercept therapy. Lancet
13. Mohan AK, Edwards ET, Cote TR, et al. Drug induced systemic lupus erythematosus and TNF-α blockers. Lancet
14. Cairns AP, Duncan MKJ, Hinder AE, et al. New onset systemic lupus erythematosus in a patient receiving etanercept for rheumatoid arthritis. Ann Rheum Dis
15. Jonsdottir T, Hariu A, van Vollenhoven A, et al. Treatment with TNF-antagonists is associated with an increasing frequency of anticardiolipin antibodies (ACLA)—ACLA positivity predicts worse clinical outcomes. Arthritis Rheum
16. Ferraccioli GF, Mecchia F, Di Poi E, et al. Anticardiolipin antibodies in rheumatoid arthritis patients treated with etanercept or conventional combination therapy: direct and indirect evidence of a possible association with infections. Ann Rheum Dis
17. Day R. Adverse reactions to TNFα inhibitors in rheumatoid arthritis. Lancet
18. Weinblatt M, Keystone EC, Furst DE, et al. Adalimumab a fully human anti-tumor necrosis factor α monoclonal antibody for treatment of rheumatoid arthritis in patients taking concomitant methotrexate. The ARMADA trial. Arthritis Rheum
19. Machold KP, Smolen JS. Adalimumab a new TNFα antibody for treatment of inflammatory joint disease. Expert Opin Biol Ther
20. Cairns AP, Crockard AD, McConnell JR, et al. Reduced expression of CD44 on monocytes and neutrophils in systemic lupus erythematosus: relations with apoptotic neutrophils and disease activity. Ann Rheum Dis
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