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Proton pump inhibitors and subacute cutaneous lupus erythematosus: an under‐recognized phenomenon?

In this month’s issue of BJD, Sandholdt et al. publish the largest case series to date of drug-induced subacute cutaneous lupus erythematosus (DI-SCLE) triggered by proton pump inhibitors (PPIs). This retrospective case note review of a Danish cohort identified 24 new cases, in addition to eight previously published, of DI-SCLE linked to PPI prescription over a 19-year period. Alongside the more usual DI-SCLE culprit medicines, such as antihypertensives and terbinafine, PPIs are also readily and widely prescribed in general practice. Used for the treatment of peptic ulcer disease and gastro-oesophageal reflux disease, the PPI class of drugs is among the most profitable for drug companies and is often considered to have few side-effects. As dermatologists we commonly prescribe PPIs as gastric cover for prednisolone therapy, often in those with pre-existing autoimmune conditions. This paper by Sandholdt et al. draws our attention to an important drug side-effect that may impact on our prescribing practice. Sandholdt et al. observed that PPI-induced SCLE had a similar antibody profile to other drug-induced SCLE. The strongest association was with anti-Ro/SSA antibodies, with 73% of patients positive; 36% had anti-La/SSB antibodies and only 8% had antihistone antibodies. Overall, 61% of cases were positive for antinuclear antibodies. This finding is in keeping with a previous systematic review by Lowe et al. of DI-SCLE, which estimated an anti-Ro/SSA positivity of 80% across cases from all causative drugs. Similarly, both papers have observed that despite clinical resolution of symptoms on stopping the offending agent, anti-Ro positivity seems to persist. It has been shown that Ro and La autoantibodies are present in healthy individuals without symptoms of autoimmune disease. It is likely to be this asymptomatic unidentified population that is at particular risk of developing DI-SCLE. To support this hypothesis Arbuckle et al., in their 2003 paper, proposed the concept of crescendo autoimmunity. In the context of DI-SCLE this hypothesis describes a scenario in which an asymptomatic individual with anti-Ro antibodies is then exposed to the offending drug, which leads to an overt autoimmune presentation of SCLE. The mechanism for this is poorly understood, but may involve the induction of a phototoxic state, or it may be through alterations in antibody/antigen expression, a cytotoxic response. This interaction does not seem to occur immediately on initiation of the drug, but is often after a prolonged latency period. In PPI-induced SCLE, Sandholdt et al. found the average time from starting the drug to the onset of symptoms was 8 months, which can lead to diagnostic difficulty. To circumvent this serious interaction, all patients could be screened for Ro and La autoantibodies prior to commencing a PPI. However, the rarity of the complication and the cost and potential implications of the investigation would not warrant regular screening. The published consensus on DI-SCLE is that it is indistinguishable from other forms of SCLE clinically, histologically and immunologically, but it does occur more commonly in the elderly female population. The total number of published cases of PPI-induced SCLE remains small, and therefore this rare side-effect should not prohibit PPI prescription in cases where it is clearly indicated. However, physicians should be aware that in patients with known Ro or La autoantibodies, or the associated conditions of systemic lupus erythematosus, SCLE or Sj€ ogren syndrome, caution should be practised in prescribing PPIs as they may lead to a flare or de novo presentation of SCLE. PPIs should also be added to our list of usual suspects when considering possible drug culprits for a new presentation of SCLE.