Case of erythema elevatum diutinum associated with IgA paraproteinemia successfully controlled with thalidomide and plasma exchange

Erythema elevatum diutinum (EED) is a rare chronic inflammatory dermatosis often associated with monoclonal IgA gammopathy and myeloma [1]. An 83-year-old man presented with multiple, symmetric, fibrotic, hyperkeratotic/crusted/ulcerated, pruritic/painful, firm, purplish-red nodules on the extensor surfaces of the interphalangeal, metacarpophalangeal and metatarsophalangeal joints, elbows and knees (Fig. 1) that appeared five years earlier. Skin biopsy showed a leukocytoclastic vasculitis consistent with EED. The patient was treated for one year with Dapsone, with progressive worsening. At that time, the laboratory tests showed an IgA kappa monoclonal protein. The serum IgA level was 760 mg/dL. Neither monoclonal urinary components nor Bence Jones proteinuria were found. Paraproteinemia was thus consistent with monoclonal gammopathy of undetermined significance (MGUS). Three weekly sessions of plasma exchange (PLEX) were introduced during the first and second week, two exchanges/week from the 3rd to 8th week, one exchange/week from the 9th to 12th week. From the 13th week we added thalidomide 200 mg/day and 100 mg/day alternatively and we reduced PLEX to one exchange every 2 weeks. The association of the two drugs was decided owing to the sudden and marked increase in IgA (520 mg/dL). PLEX was then discontinued while thalidomide was continued as monotherapy. Thalidomide was discontinued and PLEX was restarted from the 22nd to the 35th month. The rationale of returning to PLEX treatment was to avoid the neurotoxicity of thalidomide. Following 18 plasma exchanges the IgA level decreased from 760 to 356 mg/dL and the severe (+++) skin lesions significantly improved (++). Following the association of thalidomide with PLEX, from the 4th to 9th month, the skin lesions further improved, without flares (+), and the IgA levels were slightly above the normal range (Fig. 1). Subsequently, from the 10th to 21st month, the treatment with thalidomide alone (100 mg e.o.d.) allowed the cutaneous lesions to significantly improve, and to reach an IgA level slightly above the normal value (418 g/L). From the 22nd to 35th month, i.e. at the end of the therapy, treatment with PLEX alone maintained the skin lesions as well controlled, and the IgA levels around the high normal values (Fig. 1). Co-administration of both treatments from the 4th to 9th month maintained the efficacy of plasmapheresis when its frequency was reduced. The time course of the serum IgA concentration and skin lesions can be seen in Figure 2. figure Figure 1. Nodules/plaques on the extensor surfaces of the interphalangeal and metacarpophalangeal joints, at baseline (a) and after 9 months since the beginning of treatment and 6 months of the association of thalidomide with plasma exchange (PLEX) (from the 4th to 9th month) (b). figure Figure 2. Time course of serum IgA concentration and skin lesions (+++, severe; ++, moderate; +, mild) during treatment: PLEX, plasma exchange; Thal, thalidomide. aSerum IgA value at baseline (immediately before the first PLEX); Skin lesions at baseline (immediately before the first PLEX): +++ (severe, highest severity degree). bSerum IgA value after 2 months (T2) of treatment with PLEX alone; Skin lesion: ++ (moderate). c1Serum IgA value after 3 months of PLEX plus thalidomide; Skin lesions, + (mild). c2Serum IgA value after 6 months of PLEX plus thalidomide; Skin lesions, + (mild). dSerum IgA value after 21 months (T21) of treatment and after 11 months of Thal alone; Skin lesions, + (mild). eSerum IgA value after 35 months (T35) of treatment and after 15 months of PLEX alone; Skin lesions, + (mild). fTreatment from 1st month (start of treatment) to 35th month (end of treatment): PLEX, Plex alone; PLEX + Thal, 100 mg/d alternated with 200 mg/d; Thal alone, 100 mg/eod. *400 mL/dL = IgA upper normal vallue. Dapsone is the first-line treatment, but with no effects on paraproteinemia. Alternatively, other systemic drugs have been suggested for EED treatment that have antioxidant or antinflammatory and immunomodulant properties but do not influence the synthesis of paraproteins and therefore were not administered. Circulating immunocomplexes, monoclonal antibodies, cytokines and paraproteins are removed from the plasma through the PLEX that must be associated with immunosuppressive or cytotoxic therapy, in order to avoid the hyperproduction of pathological plasmatic factors. Thalidomide has an anti-angiogenic property that plays a significant role in the prevention of the progression of a more advanced form of biologic MGUS toward a multiple myeloma. Efficacy of the therapeutical modalities suggested for EED has not yet been defined owing to the limited number of cases studied [2, 3]. To our knowledge, this is a novel treatment because it is the first case of EED associated with IgA paraproteinemia treated with thalidomide. Therefore, this drug could be evaluated to control the disease, and could be useful in maintaining the results of PLEX. References 1 Comfere NI, Gibson LE. Erythema elevatum diutinum. In: Wolff K, Goldsmith LA, Katz SI, Gilehrest BA, Paller AS, Leffell DJ, eds. Fitzpatrick's Dermatology in General Medicine, 7th edn. New York: McGraw-Hill, 2008; 1616–1619. Universita di Pisa 2 Chow RK, Benny WB, Coupe RL, Dodd WA, Ongley RC. Erythema elevatum diutinum associated with IgA paraproteinemia successfully controlled with intermittent plasma exchange. Arch Dermatol 1996;132:1360–1364. CrossRef,PubMed,CAS,Web of Science® Times Cited: 20 Universita di Pisa 3 Galeone M, Arunachalam M, Bassi A, Scarfì F, Difonzo EM. Erythema elevatum diutinum. QJM 2014;107:227–228. CrossRef,PubMed,Web of Science® Times Cited: 1