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Silent thyroiditis associated with etanercept in rheumatoid arthritis
  1. E Andrés1,
  2. F-X Limbach2,
  3. B Goichot1,
  4. J Sibilia2
  1. 1Department of Internal Medicine, University Hospital Strasbourg, France
  2. 2Department of Rheumatology, University Hospital Strasbourg
  1. Correspondence to:
    Professor J Sibilia, Service de Rhumatologie, Avenue Moliére, 67 098 Strasbourg Cedex France;
    jean.sibilia{at}wanadoo.fr

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In recent years, monoclonal antibodies (infliximab) and a recombinant human tumour necrosis factor receptor (p75)-Fc fusion protein (TNFR:Fc) (etanercept) have been successfully used to treat rheumatoid arthritis (RA).1 These TNF blocking agents are now widely employed in patients with treatment resistant RA. TNF inhibitors are generally well tolerated with <0.5% of patients developing a drug induced lupus syndrome, although 4–16% may develop antibodies to double stranded DNA (dsDNA). Apart from two patients presenting autoimmune skin diseases associated with etanercept (discoid lupus and necrotising vasculitis),2 there are no other reports of well documented autoimmune disease. In this paper we describe the first case of silent autoimmune thyroiditis during TNFR:Fc treatment for severe RA.

CASE REPORT

A 43 year old woman followed up since 1991 for erosive RA had been successively treated with various disease modifying antirheumatic drugs (Allochrysine, d-penicillamine, and methotrexate) combined with low dose corticosteroids. In March 1998 she reported an important flare up despite corticosteroids (10 mg/day) and methotrexate (15 mg/week). Methotrexate was replaced by etanercept (25 mg twice a week), which led to a dramatic improvement after one month of treatment. The evaluation before TNFR-Fc treatment disclosed no evidence of thyroid disorders: the patient had no clinical features, serum thyroid stimulating hormone (TSH) and free thyroid hormones were normal, and thyroid antibodies were negative. No other autoantibody (anti-dsDNA, anticardiolipin, anti-extractable nuclear antigen (ENA)) was present except a high titre of IgM rheumatoid factor. In January 2000 the patient developed a non-tender moderate goitre. Thyroid evaluation disclosed modest hypothyroidism: serum TSH 6.3 mU/ml (normal <4.5) and serum free thyroxine (T4) 11 pmol/l (normal 11–23) (Elecsys assay). Titres of native antimicrosomal and antithyroglobulin antibodies were raised at 820 IU/ml (normal <60) and 230 IU/ml (normal <60), respectively (radioimmunoassay, Brahms). Anti-TSH receptor antibodies were negative (<5 IU/l, normal <11) (Radio Receptor Assay, Brahms) and no other autoantibodies (anti-dsDNA, anticardiolipin, anti-ENA) were found except an IgM rheumatoid factor. A technetium-99m pertechnetate thyroid scintigraphic scan showed reduced uptake.

In the absence of other known cause, the diagnosis was silent thyroiditis induced by TNFR:Fc. Etanercept treatment was completed four months after the onset of hypothyroidism, and there was no aggravation of the thyroid disorder without hormonal substitution after a year and a half of follow up.

DISCUSSION

This report describes a case of silent autoimmune thyroiditis which developed during TNFR:Fc treatment in a patient with RA without evidence of previous thyroid disorders. Thyroiditis has not to our knowledge been described as a side effect of TNFR:Fc treatment and a causal relationship cannot formally be established in our case report. However, cytokines like interferon γ or interleukin 2 often induce thyroiditis in patients with pre-existing autoimmune thyroid disease. T cell (Th1) depletion with monoclonal antibodies (Campath-1) can also lead to the development of antibody mediated thyroid autoimmunity.3 The mechanism of this effect of TNF blocking agents is not well understood, but modulation of the homing of Th1 and Th2 cells may explain the induction of autoimmune thyroiditis.4,5 In our opinion, TNFR:Fc treatment should be considered as a potential cause of drug induced autoimmune thyroiditis. Nevertheless, further studies are needed to estimate the incidence and the mechanism of this side effect.

REFERENCES

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