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

Adverse Events

Peripheral Polyneuropathy

Twenty-seven articles evaluated possible contributing factors for thalidomide peripheral polyneuropathy in patients with and without lupus. This adverse effect occurs in 15% to 80% of SLE/CLE cases.[14,15,47,60] The underlying disease, study design, and factors associated with this condition are illustrated in Table 2 and discussed below:

  1. Study design and sample size: Sixty-two percent were retrospective, and 10 studies were prospective (1 had a sample size of ≥25 SLE/CLE patients).[80]

  2. Underlying disease: Studies encompassed a variety of diseases besides CLE and SLE including oral or orogenital ulceration, graft-versus-host disease, Jessner lymphocytic infiltrate, mixed connective tissue disease, monoclonal gammopathy of undetermined significance, multiple myeloma, nodular prurigo, pyoderma gangrenosum, and recurrent erythema multiform. Eleven reports focused on CLE and SLE, and 7 of them were retrospective.

  3. Exclusion of predisposing conditions other than thalidomide: Exclusion of predisposing conditions such as B12 deficiency, alcoholism, diabetes mellitus, tuberculosis, cryoglobulinemia, HIV, lymphoma, and chemotherapy[86] were not reported in 59% of the published studies,[71,75] and the remaining reported a partial exclusion criterion.

  4. Factors associated with neurotoxicity: Initial daily dose was recognized as an associated factor in 4 studies, whereas 8 did not confirm this finding.[58,80] Cumulative dose (≥20 g)[83] and length of use (>9 months)[79] were reported as risk factors for this adverse effect, but this finding was not confirmed in other studies.[14,18] For cumulative dose, particularly 20 g or greater, 59% of the reports had not identified this as a relevant factor, and 22% reported this association. Accordingly, approximately 44% of the studies have not observed an association with length of treatment, whereas 3 prospective analyses and 1 retrospective suggested that this was an important factor (9 months). Regarding age, one-third of the reports did not observe any association, although 3 reported a tendency, and 2 others described as a relevant factor.[75,77]

  5. Neuropathy clinical presentation: Clinical polyneuropathy occurs in 15% to 80% of SLE/CLE cases.[15,60] Typically, thalidomide-induced peripheral neuropathy is symmetrical, with painful paresthesia of the hands and feet, often accompanied by sensory loss in the lower limbs.[87] Strength is usually preserved, although mild weakness has been described. Ankle jerk reflexes may be depressed or absent.[88]

  6. Polyneuropathy diagnosis by electrophysiological studies: Nerve conduction studies are the most widely used tests to evaluate thalidomide-induced neuropathy,[75] with reports of 0% to 80% abnormalities in this examination.[17,47] A 50% reduction in the amplitude of the sural sensory nerve action potential compared with baseline is considered diagnostic for sensory axonal neuropathy, and the electrophysiological abnormalities can occur even without clinical sensory symptoms.[74,75] There are also reports of motor involvement besides the classical sensory axonal pattern. Studies that evaluated reversibility of the nerve conduction after thalidomide was withdrawn included a total of 58 patients, with a reevaluation time ranging from 4 to 47 months.[18,19,54,55,57,71,75,76,79,81,84,85] In these cases, 25% improved, 25% worsened, and 50% presented stability of the nerve conduction study. Regarding clinical reversibility, a total of 230 patients were evaluated for this outcome, with more than 70% of improvement ranging from 22% to 100%.[51,73,81,85]

  7. Mechanisms of neurotoxicity: Johnson et al.[89] identified genetic variations of single-nucleotide polymorphisms associated with increased risk of thalidomide neuropathy in patients with multiple myeloma, particularly in genes related to repair mechanisms and inflammation of peripheral nerves. Other mechanisms of thalidomide neurotoxicity include its antiangiogenic effect, leading to hypoxia and ischemia of nerve fibers, direct toxic effect on the dorsal sensory ganglion, and dysregulation of neurotrophin activity through nuclear factor κB inhibition.[90] In this aspect, in a rabbit experimental model, the effect of thalidomide on the fetal development was reported to be a direct toxic effect on the neurons of the dorsal sensory ganglia, and this effect preceded the malformations in the limbs.[91] Reinforcing this possibility, a patient with nodular prurigo exposed to thalidomide presented magnetic resonance imaging abnormalities in the dorsal root ganglia, suggesting a direct toxic effect on the sensory ganglion neurons.[92]

Specialists' Approach to Thalidomide Polyneuropathy

Routine clinical and electrophysiological evaluations should focus on early diagnosis and are recommended at baseline, every 6 months and/or whenever neuropathic symptoms occur. Special attention should be taken regarding predisposing conditions such as high cumulative dose and long therapy duration. To minimize this complication, the lowest efficacious daily dose should be recommended, and most studies started with 100 mg/d with reduction as soon as a clinical response was obtained.[1,20,59] The drug should be withdrawn if clinical or electrophysiological peripheral neuropathy occurs.

Other Adverse Events of Thalidomide

Somnolence is a relevant complaint followed by dizziness, orthostatic hypotension, constipation, and temporary amenorrhea. Itchy maculopapular rash may occur within 10 to 14 days of treatment but tends to be mild and improve with dose reduction.[30] Teratogenicity is the most disturbing adverse event and occurs even with only 1 single medication dose from 34 to 50 days after conception.[87]

Cesbron et al.[93] carried out the largest multicenter retrospective study that evaluated the association of thalidomide with thrombotic events in patients with CLE and included 139 patients, with a report of 8 thrombotic events (general thrombotic risk 2.74 per 100 patient-years, arterial general thrombotic risk 1.72 per 100 patient-years, and venous general thrombotic risk 1.03 per 100 patient-years). The risk of general thrombosis was higher in patients with previous history of arterial thrombosis and hypercholesterolemia and was lower for low-dose thalidomide (50 mg/d) and for the association of HCQ and thalidomide. The general thrombotic event risk was not increased with smoking habit, low-dose glucocorticoid, antiphospholipid syndrome, or antiphospholipid (aPL) positivity.[93]

Specialists' Approach to Other Adverse Events

The high teratogenic risk implies a very strong recommendation for contraception. Men should use condom in all sexual intercourse even if they have undergone vasectomy and maintain its use for 4 weeks after the discontinuation of thalidomide.[94] In women of childbearing age, the use should be exceptional when all other options have failed. Sexual abstinence or use of 2 concomitant contraceptive methods is strictly required: one being highly effective (such as long-acting reversible contraceptive [intrauterine devices and subdermal implant] or medroxyprogesterone acetate) and other with barrier method (male/female condom). The patient should initiate the contraceptive methods at least 4 weeks before the start of the medication, throughout the treatment, and until 4 weeks after its suspension. The patient should have a 24-hour pregnancy test before starting treatment; repeat it weekly in the first month, and every 2 to 4 weeks after the first month.[94] Somnolence, dizziness, and orthostatic hypotension may be minimized by night use.

With regard to thrombosis risk, the lowest possible dose of thalidomide is recommended associated with HCQ. Antiaggregation with low-dose aspirin should be used in lupus patients with aPL. The presence of positive aPL associated to other thrombosis risk factors may require low-molecular-weight heparin in rare cases.[93]

Table 3 illustrates general recommendations for thalidomide for treatment of refractory cutaneous SLE/CLE.

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