In August 2006, a 39-year-old woman with rheumatoid arthritis (RA) was seen at the outpatient clinic for exacerbation of RA. In the previous few months, she had progressively swollen and painful joints, notably her wrists, knees, and feet. A review of her medical history revealed that in addition to an erosive, rheumatoid factor anticitrullinated protein antibody–positive RA since 1995 she had autoimmune hypothyroidism and diabetes mellitus type 1 since 1986. For these conditions she used long-acting (24 U/d) and short-acting (50 U/d) insulin and L-thyroxine (262.5 μg/d). Findings from physical examination were unremarkable except for polyarthritis (shoulders, elbows, wrists, knees, ankles, hands, and feet). Her RA disease activity score of 28 joints (DAS28) was 8.3 (low disease status, DAS28 < 3.2). Type 1 diabetes mellitus and hypothyroidism were in a well-controlled condition (hemoglobin A1c level of 6.8% [reference range, 4.0%-6.0%] [to convert to proportion, multiply by 0.01], thyrotropin (TSH) level of 1.18 mU/L [reference range, 0.35-4.70 mU/L], and free thyroxine [FT4] level of 20 pmol/L [to convert to nanograms per deciliter, divide by 12.871] [reference range, 10-23 pmol/L]). Because this patient was refractory to tumor necrosis factor–blocking agents (etanercept and infliximab) and disease-modifying antirheumatic drugs (sulfasalazine and methotrexate), B-lymphocyte depletion therapy (rituximab) was started in a 2-week cycle of 1000 mg intravenously, with the addition of 100 mg of methylprednisolone to prevent infusion-related adverse events.
After 3 months of rituximab treatment, this patient was seen at the outpatient clinic of internal medicine for hypothyroidism and diabetes. At that time there were no complaints of palpitations or weight loss. Remarkably, blood test results showed decreased TSH levels (0.24 mU/L), with a FT4 level in the high-normal range. After 5 and 6 months of treatment there was only a slight improvement of her active RA status, but blood test results revealed clinical hyperthyroidism (TSH, 0.10 mU/L; FT4, 25 pmol/L, and total triiodothyronine [T3], 3.1 nmol/L [to convert to nanograms per liter, divide by 0.0154] [reference range, 1.2-2.8 nmol/L]) (Figure, A). Both T3 and FT4 levels were elevated, indicating that the conversion of thyroxine in T3 was proceeding accurately. Differential diagnostic considerations explaining the development of hyperthyroidism can be divided intoexogenous (eg, pituitary TSH production) and endogenous (eg, Graves disease) causes. Both exogenous (as TSH levels were decreased, with inflated thyroxine levels), and endogenous (such as Graves disease) causes of hyperthyroidism seemed unlikely in this long-standing overt hypothyroid patient. Neither the L-thyroxine dosage nor smoking habits were changed, and the patient's type 1 diabetes mellitus remained in a well-controlled condition (hemoglobin A1c level of 6.5%). Another mechanism that may explain the incidence of hyperthyroidism is an increased activation of thyroid peroxidase (TPO), an enzyme catalyzing reactions for synthesis of T3 and FT4. A plausible explanation for elevated TPO activity is a drop in the level of antibodies against TPO (TPOAbs) by rituximab-induced depletion of plasma cell precursors. Indeed, TPOAbs declined to undetectable levels (as measured with the Phadia ImmunoCAP System; Phadia AB, Phadia AB, Uppsala, Sweden) after 5 months of treatment (Figure, A).
Thyroid function during 9 months of rituximab therapy. FT4 indicates free thyroxine; TPOAbs, antibodies against thyroid peroxidase; and TSH, thyrotropin. To convert FT4 to nanograms per liter, divide by 12.871.
Autoimmune hypothyroidism is characterized by lymphocytic infiltration of the thyroid and the presence of thyroid autoantibodies (eg, TPOAbs).1 Another autoimmune disease characterized by (synovial) lymphocytic infiltration is RA. Rituximab, a chimeric monoclonal antibody against CD20-positive B lymphocytes, is known to decrease synovial lymphocyte aggregates in patients with RA.2 Our hypothyroid diabetic patient with RA developed hyperthyroidism 4 months after initiating rituximab therapy. This is remarkable because rituximab is a novel therapy for patients with Graves disease.3 Interestingly, in NOD.H-2h4 mice exposed to sodium iodide–polluted water to induce spontaneous autoimmune thyroiditis, thyroid autoantibody responses could be reduced by B-cell depletion. Moreover, B-lymphocyte depletion in this murine study resulted in diminished B- and T-lymphocyte infiltration of the thyroid, thereby inhibiting the development of spontaneous autoimmune thyroiditis.4 In line with this study, our observation suggests that rituximab therapy may be beneficial for autoimmune hypothyroidism. Although this hypothesis needs confirmation in other studies, in daily clinical practice, clinicians should be aware of (transient) stimulation of thyroid function during rituximab therapy in overt hypothyroid patients.
Correspondence: Dr Nurmohamed, Departments of Internal Medicine and Rheumatology, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, the Netherlands (email@example.com).
Author Contributions:Study concept and design: Raterman, Simsek, and Nurmohamed. Acquisition of data: Raterman, Simsek, and Meesters. Analysis and interpretation of data: Raterman, Simsek, Lems, Meesters, Dijkmans, and Nurmohamed. Drafting of the manuscript: Raterman, Lems, and Nurmohamed. Critical revision of the manuscript for important intellectual content: Simsek, Lems, Meesters, Dijkmans, and Nurmohamed. Obtained funding: Dijkmans. Study supervision: Simsek, Lems, Dijkmans, and Nurmohamed.
Financial Disclosure: Dr Dijkmans has received an educational grant from Roche Nederland.
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