Correspondence *Practice for Internal Medicine, Mittweidaer Str. 11–15, 12627 Berlin, Germany

Email rheucard@gmx.de

The Case

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.¹ 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.

Figure 1 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.

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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).

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 and globulin fraction. (C) Plasmocytoma (stage IIA according to the Durie and Salmon staging system²) 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.

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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 system²) 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 and 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.

Discussion of Diagnosis

RA was diagnosed unequivocally in this patient in 1988, based on clinical symptoms and radiographic analysis. As described above, plasmocytoma was detected during the routine safety surveillance that accompanied the anti-tumor necrosis factor (TNF) therapy. Previous laboratory examinations of the globulin fraction had shown a significant M gradient; therefore, gammopathy was suspected. Follow-up examinations finally led to the diagnosis of stage IIA plasmocytoma according to the classification scheme developed by Durie and Salmon.² As an increase of the and globulin fraction had been documented 8 years earlier, we assume that the malignancy was present before the start of the adalimumab therapy. Levels of paraprotein and ₂ microglobulin were not analyzed.

Treatment and Management

Limited data exist regarding the development of multiple myeloma in patients with RA. In one study, 7 of 154 patients with multiple myeloma had concomitant rheumatoid diseases,³ and the authors concluded that RA might be a risk factor for development of multiple myeloma.

Biologics are proteins that display pharmacological activity and offer novel therapeutic options in the treatment of autoimmune diseases such as RA. One important group of biologics encompasses substances that block the actions of TNF. Adalimumab, an entirely human-derived recombinant monoclonal antibody specific to TNF, is effective for the treatment of active RA.⁴

The main reason for the introduction of adalimumab treatment in combination with methotrexate and etoricoxib was that all earlier attempts to treat the patient's progressive RA had not achieved the desired clinical effect. Anti-TNF therapy was started without our knowledge of a pre-existing malignancy. As safety is closely monitored during anti-TNF therapy, the presence of a monoclonal gammopathy was suspected soon after the initiation of this treatment and led to the interruption of the adalimumab treatment. An early stage of a plasmocytoma (stage IIA according to the Durie and Salmon staging system²) was diagnosed; this was deemed to require regular follow-up, but not treatment.

Careful investigation of the patient's medical history revealed documentation of an increased and globulin fraction 8 years before the start of the anti-TNF therapy. Owing to the short duration of the earlier azathioprine treatment, an association of this anti-TNF treatment with the development of a lymphoproliferative disease is unlikely.

Although the efficacy of adalimumab for treating RA is unquestioned, knowledge is still limited with regard to safety of this treatment; for example, cases of malignancies, such as lymphoma,⁴ have occasionally been observed in patients treated with TNF-blocking agents.⁵ The incidence of lymphoma was reported to be increased in patients with highly-active RA, but it is not clear whether this is due to the nature of RA or whether TNF blockade has a role in lymphoma development.^{6, 7} One report that summarized all available information on the safety of adalimumab showed a standardized incidence ratio for lymphoma of 3.19, which is close to the range observed for the general RA population (approximately 2.0–2.7).⁸ Data from controlled clinical trials also indicated no difference in the rate of lymphoma between the adalimumab groups and the control groups (1.1 per 1000 patient-years in both groups).⁹

For patients with RA who had a pre-existing cancer, Watson et al.¹⁰ attempted to assess the potential malignancy risk associated with anti-TNF therapy. Analysis of data from 10,000 patients with RA on the British Society of Rheumatology Biologics Register resulted in an incidence rate ratio of 2.5 (95% CI 1.2–5.8). This report indicated that patients with a malignancy prior to the initiation of anti-TNF therapy had a slightly higher risk of developing a further malignancy than patients without a previous malignancy. Wolfe and Michaud¹¹ analyzed the association between malignancy and biologic therapy in 13,000 patients with RA, and reported that therapy with biologic agents might be associated with a slightly increased risk of nonmelanotic skin cancer (odds ratio 1.5, 95% CI 1.2–1.8) and melanoma (odds ratio 2.3, 95% CI 0.9–5.4); however, the authors found no increased risk of solid tumors or lymphoproliferative malignancies.

No deterioration of the multiple myeloma was detected in this patient despite treatment with adalimumab, which clearly provided relief from symptoms of RA. This observation is in line with several reports. Askling et al.¹² concluded that treatment with TNF antagonists was not associated with increased lymphoma risk in patients with RA. Similarly, Setoguchi et al.¹³ found no clinically-relevant increase of cancer risk in patients treated with biologics (etanercept, infliximab, adalimumab, or anakrina) compared with patients treated with standard disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate. Baecklund et al.¹⁴ showed that the increased lymphoma risk observed in patients with RA is associated with inflammatory activity, rather than treatments.

It has to be considered that patients with multiple myeloma could benefit from anti-TNF therapy. Jourdan et al.¹⁵ demonstrated that TNF is a survival factor for myeloma cell lines, inducing their cell cycle and promoting their long-term growth. Because excess TNF is produced in patients with multiple myeloma, and since this is associated with a poor prognosis, these results suggest that anti-TNF therapy might be beneficial for patients with this disease.

On the basis of all available data, the question of whether anti-TNF therapy can be initiated in individuals with previous malignancies is still not solved and requires careful consideration.¹⁶ In the current patient, treatment with adalimumab was shown to be safe despite the presence of a malignancy, suggesting that there is no direct association between treatment with TNF blockers and occurrence of multiple myeloma. If adalimumab had triggered the change from a pre-malignant form to the plasmocytoma, we would have expected further deteriorations due to the continuous anti-TNF therapy. In contrast, we observed a positive outcome, both with respect to the signs of RA and the concomitant parameters.

Conclusions

If patients are provided with close supervision, treatment of RA with TNF antagonists such as adalimumab might be safe and effective in patients with certain malignancies. Futhermore, for patients with severe RA-related complaints, the beneficial effect of anti-TNF treatment might outweigh the slightly increased risk of developing malignancy. More detailed knowledge might be acquired in a systematic clinical study on this subject.

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