Darier's disease and rheumatoid arthritis: a new association and a review of the literature.

Abstract

Dear Editor, Darier's disease (DD), also known as Darier–White's disease or keratosis follicularis, is a rare autosomal genodermatosis, characterized by an altered differentiation and acantholysis of keratinocytes. Currently, some reports describe the co-occurrence of this skin disorder with different rheumatic diseases, suggesting a possible pathogenetic link between DD and autoimmunity. Here, we want to introduce our case that could represent, to our knowledge, the first possible case of DD associated with rheumatoid arthritis (RA). A 45-year old woman came to our attention for the onset of persistent articular pain, previously identified as RA. In anamnesis, she reported in puberty a histological diagnosis of DD. Physical examination showed swelling and pain of the wrists and right knee, together with the presence of small keratotic papules, localized in the scalp, retroauricular folds, back, arms and legs (Fig. 1). Laboratory findings confirmed the rheumatologic diagnosis, showing the presence of elevated inflammatory indices (erythrocyte sedimentation rate 97 mm/h, C-reactive protein 26.4 mg/dL, normal 3) and a mild anemia. Rheumatoid factor and anti-cyclic citrullinated peptide antibodies were highly positive. On the basis of the elevated disease activity (Disease Activity Score of 28 joints – CPR 5.24), treatment with leflunomide and nonsteroidal anti-inflammatory drugs (NSAIDs) (i.e., diclofenac) was promptly started, with initial improvement, lasting for 6 months. With the succeeding worsening of articular symptoms, associated with highly active scores, defined by disease activity indices, a therapy with certolizumab pegol was initiated, determining clinical articular improvement without response of the cutaneous lesions, that underwent regression with NSAIDs. DD is a rare skin disorder, affecting both sexes and all ethnic groups, with a prevalence ranging from 1 in 30 000 to 1 in 50 000 and onset in puberty. Penetrance is complete with an extreme variability in terms of expression within family components. The responsible gene is ATP2A2, found on the long arm of the 12th chromosome (12q23–24), which encodes SERCA2 (isoform of Ca++ ATPase of the sarcoplasmic reticulum).1 Clinically, the altered Ca++ pump leads to the formation of greasy keratotic papules, skin-colored or yellow-brown, isolated or confluent in plaques, localized in seborrheic areas of the upper trunk, folds, neck, and scalp. Nail abnormalities can also be associated, consisting in red longitudinal stripes, splitting and a V-shaped nick at the free margin of the nail. These findings can simulate the appearance of psoriatic arthritis or SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis). Moreover, DD is associated with neuropsychiatric abnormalities that include epilepsy, mild mental retardation, bipolar disease and schizophrenia.2 Histology examination shows two major findings: acantholysis and dyskeratosis. The former defines a loss of intercellular adhesion leading to suprabasal cleft, while the latter consists of abnormal keratinization associated with round keratinocytes (i.e., corps ronds), that probably correspond to apoptotic cells.3, 4 Hence, in the diagnostic process, it is quite hard to discriminate between DD and psoriasis, starting from the skin lesions. Recently, with the publication of some case reports, a new hypothetical link between DD and rheumatic diseases has been proposed. In 1979, Petera et al.5 described the first case of co-occurrence with chronic polyarthritis. Afterward, scientific data presented a case combined with Sjӧgren's syndrome,6 three cases of co-occurrence with spondyloarthritis7-9 and a case with systemic lupus erythematosus.10 We here describe a case of seropositive RA (treated with tumor necrosis factor [TNF]-alpha inhibitor) that developed in a patient with DD. Currently, there are no similar clinical cases reported in the literature, although the hypothesis could be advanced that skin disorders predispose arthritis development, as described in psoriasis and SAPHO syndrome. According to this theory, in genetically predisposed subjects, the skin bacterial colonization could represent the environmental trigger initiating the articular damage. Further, the increase in prostaglandins secondary to the rheumatic disease could determine the typical DD follicular papules, explaining why in our case cutaneous lesions did not respond to anti-TNF-alpha treatment, but responded to NSAIDs. In conclusion, since correlations between rheumatic diseases and DD can occur, in presence of skin lesions a careful articular investigation is mandatory in a good clinical practice. FP was involved in conception, design, acquisition, drafting and reviewing the manuscript. GS and MB were involved in interpretation of data, drafting and reviewing the manuscript for important intellectual concept. AA was involved in drafting and reviewing the manuscript for important intellectual concept.