Summary and the Case
Background: We report on a patient with rheumatoid arthritis (RA) who was treated with adalimumab and retrospectively diagnosed as having a multiple myeloma.
Investigations: In addition to the determination of clinical symptoms, investigations included radiography of the thorax, spine, hands and feet, arthrosonography, determination of laboratory parameters (including C-reactive protein levels and presence of antibodies against cyclic citrullinated peptide), cytogenetics and electrocardiography.
Diagnosis: RA was initially diagnosed in 1988. Stage II and stage III RA were diagnosed for the left and right foot, respectively, in 1996. Joints of both hands were diagnosed with stage I RA; both wrists and some finger joints showed signs of synovitis. Plasmocytoma was diagnosed in 2004; however, investigation of medical records revealed evidence of multiple myeloma 8 years earlier, in 1996.
Management: RA was originally treated with gold, sulfasalazine, azathioprin and glucocorticoid. Methotrexate was later used in addition to cortisone and then in combination with a selective cyclo-oxygenase-2 inhibitor. A combination therapy consisting of adalimumab (40 mg every 2 weeks), methotrexate (15 mg weekly) and a cyclo-oxygenase-2 inhibitor (rofecoxib 25 mg daily until July 2004, etoricoxib 90 mg daily from October 2004) was started in November 2003. Adalimumab therapy was interrupted for 6 months owing to safety concerns, but was resumed after a careful risk–benefit assessment.
The patient was first diagnosed with rheumatoid arthritis (RA) in 1988 when he was 48 years old. He was positive for rheumatoid factor and displayed arthralgia and swollen joints in both hands (Figure 1), followed by complaints in both knee joints. Synovectomies were performed in 1989 (left knee) and 1994 (right knee). In 1996 (at 56 years of age), RA was diagnosed as stage II and stage III in the patient's left and right foot, respectively, as well as stage I in the joints of both hands. Stages of progression were classified as described by Steinbrocker and colleagues. Signs of synovitis were present in both wrists and some finger joints (metacarpophalangeal joints III and IV and proximal interphalangeal joints III and IV in the left hand; metacarpophalangeal joints III, IV and V and distal interphalangeal joint II in the right hand). Arthroplasty of the left knee was performed in 2003.
Photographs of the patient's hands show synovitis of the metacarpophalangeal joints (more pronounced on the right hand) and the proximal interphalangeal joints, which is indicative of rheumatoid arthritis.
Following diagnosis, the patient was treated with gold and sulfasalazine, in combination with glucocorticoid during active phases of disease. All treatments failed to prevent further disease progression, as assessed by clinical symptoms and radiographic analysis. Treatment with NSAIDS, for example diclofenac, was contraindicated: these drugs would not have been well tolerated as the patient had undergone a Billroth II gastrectomy in 1980. Azathioprine (150 mg daily) was administered between April and August 1996; however, this treatment proved to be ineffective, with increased activity of RA during this period. Methotrexate was used in addition to glucocorticoid (Urbason®, Sanofi-Aventis, Bad Soden, Germany; 8 mg daily) from 1996 to 1998 and then in combination with a selective cyclo-oxygenase-2 (COX2) inhibitor (rofecoxib 25 mg daily), which helped to relieve pain.
Adalimumab (40 mg every 2 weeks) was introduced, in addition to methotrexate (15 mg weekly) and a COX2 inhibitor (rofecoxib 25 mg daily until July 2004, etoricoxib 90 mg daily from October 2004), in November 2003. This combination therapy resulted in a considerable improvement of the patient's condition: 1 month after inclusion of adalimumab in the therapy regimen, the number of tender/swollen joints had decreased from 8/8 to 1/5. Despite this considerable improvement, a corresponding decrease in the 28 joint disease activity score (DAS28) was less evident (5.3 before adalimumab therapy, 4.7 after 4 weeks of adalimumab therapy) owing to a high erythrocyte sedimentation rate (Figure 2).
Timeline (in years) showing RA diagnosis, adalimumab treatment (shaded red), clinical symptoms of RA, and signs and diagnosis of multiple myeloma.
(A) RA was diagnosed in 1988. (B) Electrophoresis showed an increase of the β and γ globulin fraction. (C) Plasmocytoma (stage IIA according to the Durie and Salmon staging system) was diagnosed in June 2004. (D) No deterioration of the multiple myeloma was observed in follow-up examinations. Abbreviations: DAS28, 28 joint disease activity score; RA, rheumatoid arthritis.
In June 2004, monoclonal gammopathy was revealed by the close surveillance of safety parameters that accompanied adalimumab administration, leading to discontinuation of this treatment in July 2004. Early-stage plasmocytoma (stage IIA according to the Durie and Salmon staging system) was diagnosed. The plasmocytoma required close follow-up, but did not need treatment. Careful investigation of the patient's medical history revealed that an increase in the β and γ globulin fraction had been documented in 1996. This was considered indicative of pre-stage multiple myeloma. Detailed cytogenetics, performed in December 2004, showed a karyogram with partly-missing Y chromosomes, which is considered a normal, age-associated phenomenon in men.
Unfortunately, despite taking methotrexate and a COX2 inhibitor on a regular basis, the patient experienced considerable worsening of his RA symptoms, indicated by 12 tender and 8 swollen joints and an increase in DAS28 from 4.7 to 6.3. There was, therefore, an urgent need for additional immunosuppresive therapy. Adalimumab treatment was reintroduced in January 2005.
For safety reasons, the patient has been closely monitored since the resumption of adalimumab therapy, and attends follow-up visits every 3 months. The plasmocytoma has neither changed nor deteriorated, and does not require any treatment. Laboratory parameters, such as complete blood count and levels of serum creatinine and urinary protein, have never indicated leukocytopenia or proteinuria. A slight anemia, present for several years and thought to be caused by the activity of inflammatory RA and concomitant disease, has slightly improved following treatment with adalimumab. Immunoglobulins were recorded at levels between 22.4 g/l and 27.0 g/l, and showed no tendency to decrease. The results of the cytogenetics, performed in 2004 to diagnose the plasmocytoma and afterwards for annual follow-up, were not indicative of clonal aberration. No Bence Jones protein (a measure of worsening prognosis) or any other monoclonal immunoglobulins were detected in the patient's urine at the follow-up visits performed in January 2006 and January 2007. The initial bone marrow puncture, performed in 2004 during the diagnostic work-up for plasmocytoma, had shown an infiltration rate of 20% of plasma cells; the infiltration rate was slightly lower (15%) at the follow-up appointment in January 2007.
Our careful risk–benefit analysis determined that this patient had no contraindications for reintroduction of adalimumab. As a result, combination therapy of adalimumab, methotrexate and the COX2 inhibitor, etoricoxib, was reintroduced in January 2005. The patient improved considerably, as confirmed by a decrease of his DAS28 to a value of 2.9 in March 2005 (Figure 2). This is classified as a good response to therapy according to the European League Against Rheumatism (EULAR) response criteria.
Nat Clin Pract Rheumatol. 2008;4(4):218-221. © 2008
Nature Publishing Group
Cite this: Safe Adalimumab Therapy for Rheumatoid Arthritis in a Patient With Pre-existing Multiple Myeloma - Medscape - Apr 01, 2008.