From
`
`www.bloodjournal.org
`
`
`
`on April 18, 2017. by guest
`
`For personal use only.
`
`1970
`
`CORRESPONDENCE
`
`ORAL IRON CHELATOR L1 AND AUTOIMMUNITY
`
`To the Editor:
`
`As Brincnham 1 has reviewed in detail, the use of the oral iron
`chelator LI has been associated with significant clinical and animal
`t0xicity. One of the more controversial issues surrounding the human
`use of LI has been the possible development of autoimmune phe(cid:173)
`nomena as manifested by development of autoantibodies such as
`antinuclear antibodies (ANA).
`The Canadian group investigating LI did not describe any im(cid:173)
`munologic abnormalities in their initial report,2 but laier reported
`positive ANA in 5 of 12 thalassemics with negative antibodies to
`double-stranded DNA (AdsDNA) and antibodies to histones (AHA)
`in all before starting LI ,3 after we reported possible drug-induced
`lupus in a patient taking Ll.4 The phase II LI trial report on 52
`thalassemics in India showed no "'significant toxicity" on "extensive
`clinical and laboratory monitoring" of several organ systems and
`functions.5 An update of the Indian trial6 then reported ANA-posi(cid:173)
`tivity in JO of 52 ( 19.2%) thalassemics on LI and in 12 of83 ( 14.5%)
`thalassemics on LI.
`It is surprising that neither Al-Refaie et al7 nor Agarwal et al6
`mention AHA in their patients on LI who developed ANA because
`AHA arc supposed to be specific for drug-induced lupus,8 and the
`triad of positive ANA and AHA. and negative AdsDNA is typical of
`drug-induced lupus.a
`To address the question of autoimmunity in transfusion-dependent
`thalassemia. we investigated 90 patients with thalassemia major for
`the occurrence of autoantibodies.9•10 ANA were detected in 7 of 27
`(25.9%) patients on LI , and in 2 of 63 (3.2%) patients not on LI (P
`< .01}. AHA were seen in 4 of7 patients on LI with positive ANA,
`and in neither of the 2 not receiving Li (P < .03). AdsDNA were
`undetectable in all patients with positive ANA. Five months after
`discontinuation of LI , one of the patients with positive ANA and
`
`AHA became negative for both. and four months after discontinuation
`of LI . another patient with a positive ANA and a negative AHA
`became negative for ANA.
`Our investigations show that while there is a small amount of
`background ANA-positivity in patients with thalassemia major, AHA
`are always absent. The frequency of ANA-positivity is significantly
`higher in thalassemics re<:eiving LI , some of whom also have positive
`AHA. consistent with drug-induced lupus.8 The development of ANA
`may precede the development of AHA as shown by the AHA-negative
`patient whose ANA became negative after discontinuation of LI.
`While the exact mechanism and significance remain unknown. LI
`seems to cause significant autoimmune phenomena in humans that
`may be reversible if the drug is stopped early enough but may progress
`to symptomatic systemic lupus erythematosus (SLE). The human
`use of LI should be very cautious and only under careful monitoring.
`
`JA YESH MEHTA
`SEEMA SINGHAL
`A.C. MEHTA
`Blood Research Cemre
`Bombay, India
`
`REFERENCES
`I. Brittenham GM: Development of iron-chelating agents for
`clinical use. Blood 80:569, 1992
`2. Olivieri NF, Koren G, Hermann C, Bentur Y. Chung D. Klein
`J. St Louis P, Freedman MH, McClelland RA, Templeton OM:
`Comparison of oral iron chelator LI and desferrioxamine in iron(cid:173)
`loaded patients. Lancet 336: 1275, 1990
`3. Mehta J, Singhal S, Revankar R. Walvalkar A, Chablani A,
`Mehta BC: Fatal systemic lupus erythematosus in patient taking oral
`iron chelator LI. Lancet 337:298. 1991
`
`
`1 of 4
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1035
`
`

`

`From
`
`www.bloodjournal.org
`
`
`
`on April 18, 2017. by guest
`
`For personal use only.
`
`CORRESPONDENCE
`
`1971
`
`4. Olivieri NF, Koren G, Freedman MH, Roifman C: Rarity of
`systemic lupus erythematosus after oral iron chelator LI. Lancet 337:
`924, 1991
`5. Agarwal MB, Gupte SS, Viswanathan C, Vasandani D, Puniyani
`RR, Ramanathan J, Shah S: Phase II trial of 1-2, dimethyl-3-hy(cid:173)
`droxypyrid-4-one (LI) the oral iron chelator in 52 patients of trans(cid:173)
`fusion dependent thalassaemia. Blood 76:52a, 1990 (abstr, suppl I)
`6. Agarwal MB, Gupte SS, Viswanathan C, Vasandani D, Ra(cid:173)
`manathan J, Desai N, Puniyani RR, Chhablani AT: Long-term as(cid:173)
`sessment of efficacy and safety of Ll, an oral iron cbelator, in trans(cid:173)
`fusion dependent thalassaemia: Indian trial. Br J Haematol 82:460,
`1992
`7. Al-Refaie FN, Wonke B, Hoffbrand AV, Wickens DG, Nortey
`
`P, Kontoghiorghes OJ: Efficacy and possible adverse effects of the
`oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (LI) in thal(cid:173)
`assemia major. Blood 80:593, 1992
`8. Hahn BH: Systemic lupus erythematosus, in Wilson JD,
`Braunwald E, lsselbacher KJ, Petersdorf RG, Martin JB, Fauci AS,
`Root RK (eds): Harrison's Principles of Internal Medicine (ed 12).
`New York, NY, McGraw-Hill, 1990, p 1432
`9. Mehta J, Singhal S, Chablani A, Revankar R, Walvalkar A:
`LI-induced lupus erythematosus. Indian J Hematol Blood Transf 9:
`33, 1991
`10. Mehta J, Chablani A, Reporter R, Singhal S, Mehta BC: Au(cid:173)
`toantibodies in thalassaemia major: Relationship with oral iron che(cid:173)
`lator LI. J Assoc Physicians India (accepted for publication)
`
`RESPONSE
`
`Dr Mehta and colleagues raise the issue of a systemic lupus ery(cid:173)
`thematosus (SLE) syndrome that might be induced by the oral iron
`chelator L1. This group has previously reported on a patient with
`thalassemia major who died when taking L1 and they suggested that
`an SLE-like syndrome was present. This association remains unsub(cid:173)
`stantiated. The patient died on the second day of high-dose methyl
`prednisolone therapy; this treatment, as Berdoukas1 has suggested,
`may have caused sudden cardiac decompensation. This is more likely
`to occur in a patient with pre-existing heart disease secondary to iron
`overload. It is also possible that septicemia may have contributed.
`Therefore, we agree with Berdoukas1 that the positive antinuclear
`antibody test in this patient is likely to have been incidental.
`We have monitored the antinuclear (ANA) and rheumatoid (RhF)
`factors both before and during L1 therapy in the patients we studied
`in our two long-term trials at the Royal Free Hospital. In the first
`trial of 13 patients we reported an increase in the titers of RhF in
`two patients (1/80 to 1/160, 1/80 to 1/640) and no change in the
`incidence or titre of ANA.2 In the second trial of 11 patients there
`was no change in the incidence or titer ofRhF and a slight increase
`in the incidence and titre of ANA. Initially two patients were ANA
`positive (1/160, 1/40) and finally four patients were positive (1/320
`[one patient] and 1/40 [three patients]).3 If only those patients with
`clearly positive ANA (titer > 1/80) are considered, there was only a
`change in titer in one patient and no change in incidence. We have
`been prepared to measure antibodies to double-stranded DNA
`(dsDNA) and antihistone antibodies (AHA) in any patient developing
`a significantly positive ANA during L 1 therapy, but no patient has
`developed this condition. Agarwal et a1• reported similar findings in
`earlier reports that have recently been updated. They found an increase
`in the incidence of positive (> l /80) ANA from an initial incidence
`of 11.5% (6 of 52 patients) to a final incidence of 19.2% (10 of 52
`patients). There was also a slight increase in the incidence of positive
`(> 1/80) RhF from 7. 7% to 11.5%. There was no anti-dsDNA positivity
`in any patient and AHA was not tested. In none of the above trials
`was there a correlation between musculoskeletal symptoms that oc(cid:173)
`curred in some of the patients and the change in the autoantibody
`status and no other evidence of SLE was observed.
`None of the 12 patients studied by Olivieri et als who received L1
`for up to 12 months developed positive autoantibody tests while on
`L1 therapy. Before the commencement ofL1 three were ANA positive,
`three were RhF positive, and two were positive for both. None of
`these patients developed AHA or anti-dsDNA antibody during the
`trial. More recently, Berkovitch et al6 reported knee joint pain in 3
`of the 15 patients who had received L1 for 12 to 30 months. ANA
`converted from negative to positive in a11 three patients but has re·
`mained positive in only one patient despite continuation of L1. Ini-
`
`tially, 4 of the 12 asymptomatic patients bad positive ANA and one
`has remained positive. RhF was initially positive in 5 o(the 12 patients
`and remained positive in 4 patients. Anti-dsDNA and AHA were
`negative in the 15 patients throughout the trial. Fifty-three desfer(cid:173)
`rioxamine-treated patients with thalassemia major were also studied.
`Seventeen (32%) were found to have joint symptoms. Autoantibody
`results were obtainable on 14 of the 17 patients. Three had positive
`ANA {21%) and one had positive RhF (7%).
`Therefore, weakly positive ANA and RhF tests are not infrequent
`findi~ in patients with thalassemia major whether they are receiving
`L, or desferrioxamine. In some studies there appears to be a small
`increase in the incidence and titer of these antibodies in a minority
`of patients receiving L1 with no association with other symptoms
`suggestive of SLE. It is clearly necessary to monitor for these auto·
`antibodies and for other immune abnormalities in patients receiving
`L1 in long-term human trials. The question of whether an Li-induced
`SLE syndrome occurs remains unproven.
`
`F.N. AL-REFAIE
`A.V. HOFFBRAND
`P. NORTEY
`Department of Haematology
`The Royal Free Hospital
`B. WONKE
`Department of Haematology
`Whittington Hospital
`D.G. WICKENS
`Department of Chemical Pathology
`Whittington Hospital
`London, UK
`
`REFERENCES
`I. Berdoukas V: Antinuclear antibodies in patients taking L,.
`Lancet 337:672, 1991
`2. Bartlett AN, HofJbrand AV, Kontoghiorghes GJ: Long term
`trial with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-
`one(L1) (II. Clinical Observations). Br J Haematol 76:301, 1990
`3. Al-Refaie FN, Wonke B, HofJbrand AV, Wickens DG, Nortey
`P, Kontoghiorghes GJ: Efficacy and possible adverse effects of the
`oral iron chelator I ,2,dimethyl-3-hydroxypyrid-4-one(L1) in thalas(cid:173)
`saemia major. Blood 80:3:593, 1992
`4. Agarwal MB, Gupte SS, Viswanthan C, Vasandani D, Raman(cid:173)
`than J, Desai N, Puniyani RR, Chhablani AT: Long-term assessment
`
`
`2 of 4
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1035
`
`

`

`From
`
`www.bloodjournal.org
`
`
`
`on April 18, 2017. by guest
`
`For personal use only.
`
`1972
`
`CORRESPONDENCE
`
`of efficacy and safety of L1• an oral iron chelator. in transfusion
`dependent thalassaemia: Indian trial. Br 1 Haematol 82:460. 1992
`5. Olivieri NF, Koren G. Freedman MH, Roifman C: Rarity of
`systemic lupus erythematosus after oral iron chelator L1 • Lancet 337:
`924, 1991
`
`6. Berkovitch M, Laxer RM. Matsui D, Templeton M, Pritzker
`KPH, Olivieri NF: Analysis of adverse rhumatologic effects of iron
`chelators in patients with homozygous beta thalassemia. Blood: 80:
`7a, 1992 (suppl I)
`
`
`3 of 4
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1035
`
`

`

`From
`
`www.bloodjournal.org
`
`
`
`by guest For personal use only.on April 18, 2017.
`
`
`
`
`
`1993 81: 1970-1972
`
`
`Oral iron chelator L1 and autoimmunity [letter; comment]
`
`J Mehta, S Singhal and BC Mehta
`
`Updated information and services can be found at:
`http://www.bloodjournal.org/content/81/7/1970.citation.full.html
`Articles on similar topics can be found in the following Blood collections
`
`Information about reproducing this article in parts or in its entirety may be found online at:
`http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
`
`Information about ordering reprints may be found online at:
`http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
`
`Information about subscriptions and ASH membership may be found online at:
`http://www.bloodjournal.org/site/subscriptions/index.xhtml
`
`Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American
`Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
`Copyright 2011 by The American Society of Hematology; all rights reserved.
`
`
`
`4 of 4
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1035
`
`