To the Editor:
In a followup of our report on induction of systemic lupus erythematosus (SLE) by tumor necrosis factor-α (TNF-α) inhibitors1 and the accompanying editorial2, Ye, et al describe 2 cases of anti-TNF antibody-induced lupus-like disease with anti-DNA antibody production3. Both these patients showed remission of anti-DNA but flaring of rheumatoid arthritis (RA) after discontinuation of adalimumab or infliximab. However, treatment with etanercept effectively suppressed synovitis without retriggering lupus or anti-DNA. These 2 cases of successful switching of TNF inhibitors complement 8 similar cases reported earlier. Although the effectiveness of switching from one to another TNF inhibitor may not restart SLE, we had no such success1, similar to a large number of other cases4.
As we proposed earlier, the development of lupus in these patients may have resulted from TNF blockade due to a protective effect of this cytokine in SLE5. The mechanism of TNF blocker-induced lupus may be explained by a shift from death by apoptosis to necrosis, the latter resulting in the release of nuclear debris, a trigger of antinuclear antibody (ANA) production and lupus6,7. It would be important to document whether the 2 cases of TNF inhibitor-induced lupus-like condition was accompanied only by the production of anti-dsDNA or if production of ANA was also detected by immunofluorescence8. We continue to advocate that patients treated with TNF blockers, especially those with positive ANA, should be closely monitored for development of SLE. Treatment of such cases with rituximab, recently shown to have clinical benefit not only in RA but also in SLE9, may be a safer alternative.
In a second followup of our report on the induction of SLE by TNF-α inhibitors1 and the accompanying editorial2, Chogle, et al10 describe a case of “rhupus,” i.e., an overlap syndrome between RA and lupus that developed in a patient treated with the TNF inhibitor etanercept. Their case closely resembles the second patient of our series, who was diagnosed with anti-cyclic citrullinated peptide-positive RA and developed lupus with photosensitive rash following exposure to etanercept. We agree with Chogle, et al that their case also represents TNF inhibitor-induced lupus, since the patient had no evidence of photosensitivity and rash prior to exposure to etanercept. However, we strongly disagree with the authors that their case highlights the efficacy of anti-TNF treatment in rhupus. Our 6 cases clearly illustrate that, despite temporary relief of arthritis, across the board treatment of patients with lupus or rhupus with TNF inhibitors could have life-threatening consequences, such as pericardial effusion and cardiac tamponade1,4. Therefore, TNF blockade cannot be recommended in SLE. Moreover, careful monitoring of ANA production and clinical manifestations of lupus is advocated in patients with RA failing to respond or to clinically deteriorate upon treatment with TNF inhibitors. This recommendation is consistent with several mechanistic studies indicating that TNF blockade is detrimental to autoimmunity and nephritis in humans and in animal models of lupus, as reviewed by Soforo, et al1 and Jacob and Jacob2.