Thalidomide and Lenalidomide for Refractory Systemic/Cutaneous Lupus Erythematosus Treatment

A Narrative Review of Literature for Clinical Practice

Emily Figueiredo Neves Yuki, MD; Clovis A. Silva, MD, PhD; Nadia E. Aikawa, MD, PhD; Ricardo Romiti, MD, PhD; Carlos Otto Heise, MD, PhD; Eloisa Bonfa, MD, PhD; Sandra Gofinet Pasoto, MD, PhD

Disclosures

J Clin Rheumatol. 2021;27(6):248-259. 

In This Article

Abstract and Introduction

Abstract

Background: Thalidomide has shown exceptional results in systemic/cutaneous lupus erythematosus(SLE/CLE). Recently, lenalidomide has been also prescribed for SLE/CLE treatment. Literature regarding efficacy/adverse events for these drugs is scarce with a single systematic review and meta-analysis focused solely on thalidomide for refractory cutaneous lupus subtypes.

Objective: We, therefore, addressed in this narrative review the efficacy/adverse effects of thalidomide and lenalidomide for SLE and CLE. In addition, we provide a specialist approach for clinical practice based on the available evidence.

Results: Efficacy of thalidomide for refractory cutaneous lupus treatment was demonstrated by several studies, mostly retrospective with small sample size(≤20). The frequency of peripheral polyneuropathy is controversial varying from 15–80% with no consistent data regarding cumulative dose and length of use. Drug withdrawn results in clinical partial/complete reversibility for most cases (70%). For lenalidomide, seven studies (small sample sizes) reported its efficacy for SLE/CLE with complete/partial response in all patients with a mean time to response of 3 months. Flare rate varied from 25–75% occurring 0.5–10 months after drug withdrawn. There were no reports of polyneuropathy/worsening of previous thalidomide-induced neuropathy, but most of them did not perform nerve conduction studies. Teratogenicity risk exist for both drugs and strict precautions are required.

Conclusions: Thalidomide is very efficacious as an induction therapy for patients with severe/refractory cutaneous lupus with high risk of scarring, but its longstanding use should be avoided due to neurotoxicity. Lenalidomide is a promising drug for skin lupus treatment, particularly regarding the apparent lower frequency of nerve side effects.

Introduction

Skin involvement is a very common manifestation of systemic lupus erythematosus (SLE) and may also occur without associated systemic manifestations in cutaneous lupus erythematosus (CLE). Approximately 70% to 80% of SLE patients will have cutaneous manifestations at some point along the course of the disease, with a significant proportion of debilitating and disfiguring lesions.[1] The annual incidence of CLE is approximately 2 times greater than that of SLE, reaching 4.2 per 100,000 inhabitants, whereas the annual incidence of SLE is approximately 2.9 per 100,000 inhabitants.[2–4] Both diseases predominate in young women; however, there is a lower proportion of women with CLE (3:1) compared with SLE (6:1).[4] In addition, the prevalence of SLE is higher in African American women than in white women.[5] Regarding CLE, there are few epidemiological studies in nonwhite populations, and in white-predominant populations, the prevalence of CLE is approximately 70.4 cases per 100,000 inhabitants.[4]

Cutaneous lupus lesions may be specific or nonspecific according to Gilliam and Sontheimer's[6] classification. Specific lupus erythematosus (LE) lesions may be classified as acute CLE (i.e., erythema malar, bullous lupus), subacute CLE (SCLE; which may be annular/polycyclic or psoriasiform), chronic CLE (i.e., discoid LE [DLE], hypertrophic LE [HLE], LE profundus/panniculitis, lupus chilblain), and intermittent CLE, that is, LE tumidus (LET).[6]

Acute CLE is associated with SLE and typically affects the malar regions and spares the nasolabial sulcus. Subacute CLE may be a manifestation of SLE or CLE and may also occur in drug-induced lupus. Subacute CLE presents as nonscarring papulosquamous or annular ill-defined noninfiltrative plaques in a characteristic photodistribution. It is classically associated with the anti-Ro/SSA antibody and usually presents itself as photosensitive lesions on the back, shoulders, upper limbs, and neck extensor surface.[7]

Discoid LE lesion is the most common form of cutaneous lupus and commonly presents itself as elevated erythematous plaques with a keratotic surface, with follicular hyperkeratosis (plugs), and scarring alopecia. These lesions evolve with central atrophic and hypopigmented scars and often affect the face, scalp, and ears (localized DLE), but may also be diffuse (generalized DLE). Approximately 5% to 15% of patients with DLE develop SLE, with a higher risk in those with disseminated DLE.[8] Discoid LE variants include HLE and mucosal DLE.

Lupus erythematosus profundus or LE panniculitis is a type of chronic CLE that presents as nodules or deep subcutaneous plaques, which are warmer to the touch than the surrounding areas when active and heal with lipoatrophy. These lesions are preferably located in the scalp, face, upper arms, upper thighs, and buttocks.

In turn, lupus chilblain is a rare form of chronic CLE induced by cold temperatures, presenting as erythematous papules in peripheral areas. Lupus erythematosus tumidus is characterized by erythematous edematous plaques, urticaria-like lesions, but without desquamation or follicular plugs. Photosensitivity is a dominant feature of LET, and therefore, it is most commonly located in the face and trunk. Lupus erythematosus tumidus lesions heal without atrophy or scarring and have a recurrent intermittent course.[9]

Nonspecific cutaneous manifestations of LE are diverse and may include leukocytoclastic vasculitis, urticaria-vasculitis, periungual telangiectasia, Raynaud phenomenon, and cutaneous calcinosis, among other signals.[6]

It is important to note that skin lesions of LE (mainly DLE), when not treated early, may lead to scarring on visible areas such as face, trunk, neck, scalp, and hands, leading to psychological stress, occupational incapacity, and poor health-related quality of life.[2]

The management of cutaneous manifestations of LE involves general care, topical medications, and systemic medications according to the activity and severity of the disease. In general care, photoprotection is a fundamental recommendation in all types of LE cutaneous lesions. When the disease is localized, topical treatment is the first-line therapy, and if a good response is not achieved, hydroxychloroquine (HCQ) is usually added. For the management of severe or diffuse disease, the association of topical therapy, HCQ, quinacrine, and systemic glucocorticoids is recommended as the initial treatment. In the failure of this approach, dapsone, thalidomide, and immunosuppressive drugs such as methotrexate and mycophenolate are often added.[10–12]

Thalidomide is a drug derived from glutamic acid and was initially used as a hypnotic-sedative and antiemetic agent for pregnant women. However, because of its teratogenic effect on limb development (amelia or phocomelia), it was withdrawn from the market for this purpose in 1961. On the other hand, this drug is currently used for the treatment of SLE/CLE, leprosy, human immunodeficiency virus (HIV) infection, aphthous dermatoses, Crohn disease, multiple myeloma, and prostate cancer.[13] Because of its immunomodulatory effect, thalidomide has been used to treat cutaneous activity of SLE and CLE patients, particularly in those refractory to other medications, with severe skin involvement or a contraindication to the use of immunosuppressants.[14]

The rate of complete or partial response to thalidomide is high, but polyneuropathy remains a major a concern.[15] Regarding efficacy and adverse events of this drug, studies are mainly of low quality of evidence (case reports, case series, retrospective studies, and few prospective studies with small sample size) except for 1 systematic review and meta-analysis focusing solely on thalidomide for cutaneous lupus subtypes.[16] In addition, most of these reports did not use a validated instrument for clinical response of cutaneous lupus treatment,[17] the definition of polyneuropathy was not uniform,[14] and the nonexclusion of predisposing conditions may have contributed to the variable results observed[14,18–20] and require a careful critical analysis in the interpretation of their results.

More recently, lenalidomide, an immunomodulatory agent analogous to thalidomide, has also been used for the treatment of SLE/CLE. These studies suggest a high rate of complete/partial response, low incidence of polyneuropathy, and no worsening of previous thalidomide-induced neuropathy, but the existing quality of evidence is low and limited to reports with very small sample size.[21,22]

In this narrative review, we address the efficacy, mechanisms of action, and adverse effects of thalidomide and lenalidomide for the SLE/CLE treatment with an additional specialist approach in clinical practice based on available evidence. For this purpose, we conducted a series of literature searches in the MEDLINE/PubMed database. The search strategy included a combination of medical subject headings and keywords. Search terms included "thalidomide," "lenalidomide," "systemic lupus erythematosus," and "cutaneous lupus erythematosus." The search covered the period between 1970 and 2019 and included clinical studies, animal studies, and systematic reviews. Articles selected for this article included case reports, case series, full-text articles, and review articles.

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