Thalidomide in ankylosing spondylitis F. Huang1, J.C.C. Wei2, M. Breban3 1Chinese PLA General Hospital, Beijing, ABSTRACT born to mothers exposed to thalidomide China; 2Family Medicine Department, Despite potential side effects dominat - during their first trimester of pregnancy Chia Yi Veterans Hospital, Taiwan; ed by terat ogenicity and peri p h e ra l which lead to withdrawal of the drug 3 INSERM U567 and Service de Rhumatolo- n e u ro p at hy, thalidomide has re c e n t ly f rom the market. Unfo rt u n at e ly, t h i s gie B, Hôpital Cochin, Paris, France. been used to tre at seve re anky l o s i n g did not occur before 10,000 to 12,000 Feng Huang, MD, James C.C. Wei, MD, spondylitis (AS). Over 50 patients have ch i l d ren with birth defects had been Maxime Breban, MD, PhD. been treated across several 6-12 month born from mothers exposed to the drug Please address correspondance to: open studies. A l t ogether 68% of the (6). Maxime Breban, MD, PhD, INSERM U567 and Service de Rhumatologie B, Hôpital p atients improved and the dro p - o u t Since that time however, thalidomide Cochin, 27 rue du Faubourg Saint-Jacques, rate was 19%. Inhibition of NF- B has continuously been used under re- 75014, Paris, France. and/or TNF is a putative mechanism stricted conditions, because of its re- E-mail: [email protected] for thalidomide efficacy in AS. ported efficacy on rare refractory mani- paris.fr fe s t ations involving immu n o l ogi c a l Clin Exp Rheumatol 2002; 20 (Suppl. 28): History mechanism, such as erythema nodosum S158-S161. Thalidomide ( -N-phthalimidoglutari- leprosum (ENL), chronic cutaneous lu- © Copyright CLINICAL AND EXPERIMEN- mide) is a synthetic derivative of glu- pus, Behçet’s disease, or chronic graft- TAL RHEUMATOLOGY 2002. tamic acid, which was originally devel- versus-host disease (6). More recently, oped by a German company and put on Food and Drug Administration has ap- Key words: Ankylosing spondylitis, the market as a sedative, in Canada, proved thalidomide for the treatment of spondylarthropathy, thalidomide, South America, throughout Europe and ENL in US after strict rules and regula- TNF . some countries in Asia. The drug was tions we re established between the known for rapid onset of action, lack of agency and Celgene, the US manufac- hangover, and absence of respiratory or turer. s keletal mu s cle coord i n ation impair- ment. The body’s handling of this lipo- Possible mechanism of action philic molecule is still incompletely The mechanism of action of thalido- k n own. Pharmacokinetic studies in mide is progressively broken down (6). healthy human male volunteers suggest Va rious anti-infl a m m at o ry, i m mu n o- a one compartment, first order absorp- modulatory and anti-angiogenic activi- tion and elimination model, with peak ties have been described (Table I). plasma levels reached within 4-5 hr and Most remarkably, thalidomide is a rela- a half-life of 8.7 ± 4.1 hr.Thalidomide tively weak inhibitor of TNF synthe- is metab o l i zed mainly through non- sis in vitro. At therapeutic concentra- enzymatic hydrolytic cleavage generat- tions, it reduces TNF production by ing a multitude of active intermediates approximately 40%. This TNF inhibi- with largely unknown functions (Chen tory capacity occurs at the transcrip- et al., 1989). tional level through a reduction of the In 1960, two types of major side-effects TNF mRNA half-life and is selective, we re rep o rt e d, i . e. peri p h e ral neuro- with no significant effect on cytokines pathies in patients with long-term ex- s u ch as interleukin (IL)-l, I L - 6 , a n d posure, and congenital abnormalities of granu l o cy t e - m a c ro p h a ge colony- s t i m u- the limbs (phocomelia) in ch i l d re n lating fac t o r , by human monocytes sti- Table I. Immunomodulatory and anti-inflammatory properties of thalidomide Inhibits leukocyte chemotaxis into site of inflammation Alters density of TNFa -induced adhesion molecules on leukocytes Reduces phagocytosis by polymorphonuclear leukocytes Enhances mononuclear cell production of interleukins-4 and -5; inhibits interferon-g production Inhibits production of interleukin-12 Inhibits production of TNF by monocytes and macrophages by reducing half-life of mRNA. S-158 Thalidomide in ankylosing spondylitis / F. Huang et al. mul ated with lipopoly s a c ch a ri d e wish to conceive, do not practice relia- Thalidomide use in ankylosing (LPS). ble contra c ep t i o n , or are judged by spondylitis Thalidomide’s inhibition of TNF pro- their health care provider to be inca- Up to recently, there was no effective duction is not always achieved in vivo. pable of practicing reliable contracep- therapy for patients with severe AS, re- Decreased TNFa serum concentration tion must be excluded from using tha- f ra c t o ry to non-steroidal anti-infl a m- have been described in patients suffer- lidomide. Furthermore, patient educa- matory drugs (NSAID), especially for ing from ENL or tuberculosis, treated tion about the proper and safe use of those with pre d o m i n a n t ly axial in- with thalidomide (8). However, TNFa thalidomide and serial pregnancy tests volvement. Given its pharmacological levels in blood conversely increased in are mandatory (6). properties, thalidomide has been con- t wo ra n d o m i zed controlled trials de- sidered as a putative anti-TNF agent. m o n s t rating thalidomide’s effi c a cy in Peripheral neuropathy The presence of TNF was demonstra- healing oral aphtae in the setting of Th a l i d o m i d e - a s s o c i ated peri p h e ra l ted in inflamed sacro-iliac joints of pa- HIV infection as well as reducing HIV- neuropathy has been described in detail tients affected with AS, both at messen- associated wasting. A similar observa- among the results of several large retro- ger RNA and protein levels (3). This tion was made in a study of patients spective studies published throughout observation prompted one of us to exa- with toxic ep i d e rmal necro ly s i s , i n the medical literature (6). Frequently, mine the efficacy of thalidomide in se- which outcome was adversely affected patients complain of painful paresthe- vere refractory AS. A regimen of 100- by thalidomide (18). Thus, it seems that sias and tingling sensations in the lower 300 mg/day was used.The first two thalidomide’s ability to inhibit TNFa ex t remities. Motor disturbances are patients who received the drug had a may depend on the stimulus or cellular generally mild and reversible on dis- clear benefit from thalidomide (5). Ef- source of cytokine production (6). continuation of the drug, whereas sen- ficacy of the drug concerned both axial Besides pro - i n fl a m m at o ry cy t o k i n e s sory symptoms may persist or incom- and peripheral clinical manifestations, inhibition, thalidomide exerts other in pletely resolve. The issue of irreversi- and also biological markers of inflam- vi t r o im mu n o m o d u l a ting activi t i e s , su c h bility is clouded by the retrospective mation (ESR and CRP). One of the 2 as T-cell costimu l at i o n , t h e reby en- nature of these studies and the collec- patients had prompt relapse after dis- hancing T cell response.This costimu- tion of data from patients whose condi- continuation of the drug, whereas the l at o ry effect ap p e a rs gre ater on the tions may themselves produce neuro- second was lost of follow-up. Efficacy CD8+ T cells than on the CD4+ T cells pathy. The reported incidence of tha- of thalidomide resumed after reintro- (16). There is no evidence that thalido- lidomide neuropathy varies from 0.5% ducing the treatment in the first patient. mide possesses immu n o s u p p re s s ive to 50% between series. Gardner-Med- Since this initial description, 10 addi- properties, and the drug has not been win and Powell have published guide- tional SpA patients have been treated a s s o c i ated with opportunistic infe c- lines for the use of electrophysiologic by the same author (4, 10). The dura- tions. A n t i a n gi ogenic pro p e rties of studies to monitor for neuro t ox i c i t y. tion of tre atment was 6 months fo l- thalidomide have also been found (9). They suggest baseline electromyogram lowed by a carry-over observation peri- Most recently, blocking of NF-kB acti- and nerve conduction velocity study re- od of 4 months. Of 12 patients enrolled vation through a mechanism that in- p e ated at 10 g or 6-month interva l s in this small-size open-labeled study, 5 volves the inhibition of IkB kinase was (which ever comes first) during treat- stopped thalidomide before 6 months shown with thalidomide, and was pro- ment. A decline in the sensory nerve because of side-effects. Evidence of posed as an upstream event responsible action potential of 50% or more, sub- clinical effic a c y was found in 7 of 12 pa- for the diffe rent actions of the dru g je c t i ve neurol o gic complaints at month- tients, among whom 2 achieved a re- (14).