The Effect of Rituximab on Thyroid Function and Autoimmunity

Abstract

Dear Editor:

Current evidence suggests that rituximab (RTX), a chimeric monoclonal antibody that targets and depletes the CD-20–positive B lymphocytes, is very effective in the treatment of several autoimmune and hematologic disorders (1). However, the therapeutic effect of RTX seems to be unrelated to the presence of disease-specific autoantibodies or their titers, suggesting that alterations in the antibody status or titers may not be the principal underlying mechanism (1). After the demonstration that treatment with interferon-α can induce thyroid autoimmunity and lead to alterations of thyroid function, it became apparent that other biological therapies may exert a similar effect. A six-month prospective study of patients with rheumatoid arthritis and pre-existing autoimmune thyroid disease (AITD) treated with adalimumab, an anti–tumor necrosis factor α agent, has shown a significant reduction in both thyrotropin (TSH) and anti–thyroid peroxidase (anti-TPO) antibody titers in hypothyroid patients (2). This is particularly important as AITD commonly coexists with rheumatic diseases mandating regular monitoring of thyroid function and/or the autoantibody status in these patients. Additionally, recent data suggest that peripheral B-cell depletion lasts for 4–6 months after RTX infusion (3), and B-cell peripheral and/or intrathyroidal repopulation could possibly trigger autoimmune thyroid events. The effect that a biological agent such as RTX may have on thyroid function and/or autoimmunity has not been clarified.

Therefore, we designed a prospective cohort study to investigate the effect that RTX treatment (median duration 12 months, range 6–29 months) could exert on thyroid function, autoimmunity, and morphology in 18 patients (group 1) with rheumatic diseases, with or without pre-existing AITD, for a median period of 24 months (range 6–29 months; Table 1). Thirteen patients (group 2) with rheumatic diseases who were not receiving any type of disease-modifying anti-rheumatic drugs, nonsteroidal anti-inflammatory drugs, or glucocorticoids, and 28 healthy individuals (group 3) were used as control subjects (Table 1). The participants were reviewed on a basis of every 3–6 months (median 4, range 3–7). Eleven out of the 18 group-1 patients, who were also treated with 5 mg of prednisolone daily (group 1a; RTX+P) throughout the study, were analyzed separately to delineate if there was any additional effect of concomitant steroid treatment on thyroid function and/or autoimmunity.

Table 1.

Epidemiological, Clinical, and Laboratory Characteristics of the 59 Individuals at the Beginning and End of the Study

	Group 1a (RTX+P) (n = 11)	Group 1b (RTX only) (n = 7)	Group 2 (n = 13)	Group 3 (n = 28)	p
Sex (n), female/male	9/2	7/0	11/2	25/3	n/a
Age (years)	42.0 ± 12.5	54.4 ± 20.7	56.1 ± 14.1	43.2 ± 17.9	>0.05^a
Body-mass index (kg/m²)	25.5 ± 5.5	24.5 ± 4.5	25.4 ± 3.1	24.6 ± 4.6	>0.05^a
Rheumatic disease (n)					n/a
RA	3	5	2	0
SLE	4	1	2	0
pSS	2	1	8	0
RA/SLE	1	0	0	0
pSS/SLE	1	0	1	0
Other therapies (n)					n/a
MTX	2	5	0	0
AZA	4	0	0	0
LFN	2	1	0	0
HXQ	2	1	0	0
Rheumatic disease duration from diagnosis (months)	120.0 (6–384)	60.0 (12–192)	40.0 (14–204)	0	n/a
TSH (μIU/mL)	(Normal range: 0.35–4.94 μIU/mL)
Start	1.59 ± 1.56	1.51 ± 1.08	2.01 ± 0.94	2.17 ± 0.83	>0.05^a
End	1.89 ± 1.74	1.38 ± 0.83	2.28 ± 0.91	2.15 ± 0.79	>0.05^a
fT4 (pmol/L)	(Normal range: 9.00–21.04 pmol/L)
Start	15.54 ± 3.23	13.59 ± 3.13	14.31 ± 3.70	13.08 ± 2.63	>0.05^a
End	15.82 ± 3.43	14.69 ± 3.58	14.12 ± 2.63	13.38 ± 2.28	>0.05^a
Anti-TPO (IU/mL)	(Normal range: <5.61 IU/mL)
Start	0.81 ± 0.56	19.78 ± 37.90	1.26 ± 0.89	0.84 ± 0.60	>0.05^b
End	0.77 ± 0.55	10.50 ± 16.42	0.91 ± 0.70	0.74 ± 0.43	>0.05^b
Anti-Tg (IU/mL)	(Normal range: <4.11 IU/mL)
Start	1.93 ± 2.00	3.19 ± 3.66	2.69 ± 4.33	0.94 ± 0.64	>0.05^a
End	1.76 ± 1.91	3.61 ± 3.05	3.88 ± 6.90	0.87 ± 0.59	>0.05^a
Patients with previously unknown AITD (n), start/end	2/2	3/3	2/3	0	<0.02^c
Anti-TPO positive (n)	0	3/3	0	0
Start (IU/mL)	0	45.44 ± 50.80	0	0
End (IU/mL)	0	23.96 ± 18.24^d	0	0
Anti-Tg positive (n)	2/2	2/1	2/3	0
Start (IU/mL)	5.48 ± 0.41	7.61 ± 4.93	8.78 ± 6.26	0
End (IU/mL)	5.37 ± 0.99^d	6.95 ± 4.14^d	14.36 ± 8.49^d	0

Data values are expressed as number, median (range), or mean ± standard deviation.

Analysis of variance; ^bKruskal–Wallis; ^cPearson's chi-square test; ^d T-test (p > 0.05).

AITD, autoimmune thyroid disease; anti-Tg, antithyroglobulin antibodies; anti-TPO, anti–thyroid peroxidase antibodies; AZA, azathioprine; fT4, free thyroxine; HXQ, hydroxychloroquine; LFN, leflunomide; MTX, methotrexate; n/a, not applicable; pSS, primary Sjogren's syndrome; RA, rheumatoid arthritis; RTX, rituximab; SLE, systemic lupus erythematosus; TSH, thyrotropin.

In total, 36 RTX (MabThera 100 mg/10 mL; Hoffman La Roche, Basel, Switzerland) courses were administered either as two 1000 mg (12 patients) or four 500 mg (6 patients) intravenous infusion cycles at two weekly intervals or once per week, respectively. Blood samples for measurement of TSH, free thyroxine, free tri-iodothyronine, anti-TPO, and antithyroglobulin (anti-Tg) antibodies were taken before RTX administration. For statistical analysis purposes, we considered four main study points (start, second follow-up, third follow-up, and end) to produce comparable results. No statistically significant change in mean TSH, free thyroxine, anti-TPO, and anti-Tg levels was noted between any of the three groups when compared at the different time points of the study. Similar results were obtained when the patients treated with RTX+P (group 1a) and/or RTX only (group 1b) were analyzed separately (Table 1). Furthermore, no statistically significant difference was noticed in anti-TPO and/or anti-Tg titers in patients with previously unknown AITD (only two of these patients had received oral prednisolone 5 mg daily); in one group-2 patient, anti-Tg levels increased at the end of the follow-up (start, 4.10 IU/mL; end, 10.00 IU/mL; Table 1). No patient in our cohort presented with clinical evidence of overt hypo- or hyperthyroidism. These results are in agreement with those of nine patients with Graves' disease and thyroid-associated ophthalmopathy who were treated with RTX (3). No significant change in thyroid morphology (volume, size of nodules, and echogenicity) was noticed during the study in any of the groups.

Although this is a small study, the findings suggest that irrespective of the underlying rheumatic disease, AITD status, and thyroid function in rheumatologic patients, treatment with RTX does not seem to alter thyroid function and/or thyroid autoimmunity during a considerable follow-up period of 24 months.

Footnotes

Acknowledgment

The authors would like to thank Prof. H.M. Moutsopoulos, MD, FACP, FRCP (Professor and Chairman, Department of Pathophysiology, Medical School, University of Athens), for his contribution in reviewing this work.

Disclosure Statement

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

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