Dermatology Online Journal

The safety of immunosuppressants in the treatment of psoriasis patients: Is there concern regarding those with familial lymphoproliferative disease?
Brandon G Shutty¹ DO, Daniel J Hogan² MD
Dermatology Online Journal 19 (1): 15

1. Nova Southeastern University, Largo Medical Center, Largo, Florida
2. Department of Medicine (Dermatology), Bay Pines Veteran Affairs Hospital, Bay Pines, Florida

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Abstract

Immunosuppressant drugs may increase the risk of lymphoproliferative disease (LPD) states, and additionally, the diagnosis of psoriasis may predispose to lymphoma. It is important to educate patients regarding the side effects of any treatment regimen. A positive family history of LPD disease may increase the risk of personal acquisition of LPD disease in those patients with psoriasis additionally making use of immunosuppressant therapy, such as the biologics. It is currently recommended to employ caution in those being treated with biologics who carry a high risk of developing malignancy. Those with a positive family history may fit into this category.

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Introduction

Biologics and other immunosuppressants used for the treatment of psoriasis may increase the risk of lymphoma compared to the general and psoriatic populations [1, 2]. It is clear that lymphoma risk is associated with psoriasis severity, but it is uncertain whether multiple factors have a role [3]. Lymphoma may pre-exist in patients with severe psoriasis and cutaneous lymphoma may be misdiagnosed as psoriasis [4]. It is important to inform patients regarding any side effects in psoriasis treatment regimens. For instance, complications in biologic use may include: risk of infusion reactions, life threatening and opportunistic infections (tuberculosis, fungal, or other atypical infections), malignancy such as lymphoma, as well as danger to a fetus during pregnancy [5]. It is difficult to quantify the potential risk of lymphoma in psoriasis patients treated with biologics and other immunosuppressants who additionally have a family history of lymphoproliferative disease (LPD).

Discussion

The finding of Hodgkin lymphoma (HL) in multiple family members was first recognized in 1959 and later evidence strengthened the connection between family history and the development of LPD [6]. Current literature shows an association has been proven between positive first-degree family history of cancer and a heightened incidence of Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) [7, 8, 9]. This relationship exists in about 5 percent of all family members, but the risk is greater in the first-degree. [10]. NHL, HL, and chronic lymphocytic leukemia (CLL) are now known to cluster within families such that first-degree relatives have an 8.5-fold relative risk (RR) of developing indolent NHL and a 2.6-fold RR of developing any form of LPD [11]. Another study found that about 17 percent of CLL patients and 12.5 percent of lymphoma patients have a 1st or 2nd degree relative with a related LPD [12]. In certain malignancies, such as CLL, genetic predisposition is presently the most comprehensible risk factor [12]. The finding that monozygotic twins have a heightened chance of developing either HL or NHL compared to dizygotic twins may further solidify this predisposition [13]. Whereas the association of family history of hematologic malignancy and the development of non-Hodgkin lymphoma exists, this relationship is stronger for familial aggregated lymphomas [14]. Interestingly, no survival difference was found in those with sporadic lymphomas compared to familial cases [15]. Survival differences appear to be the similar for sporadic and familial forms of CLL as well [16].

As described, genes likely play a role in the etiology of lymphoma via familial aggregation, but the pathogenesis may be more complex, involving confounding factors such as infection with Epstein-Barr virus, immunocompromised states, pesticide exposure, and certain autoimmune disorders [10, 17]. It appears that personal history, not family history, of certain autoimmune diseases confers increased future risk of lymphoma [18]. One review confirmed that family history of autoimmune conditions was not associated with increased lymphoma risk, but made no mention of family history of lymphoma itself [19]. For instance, patients with systemic lupus erythematosus (SLE) are said to have a 3 to 4 fold increased likelihood of developing B-cell malignancy related to defects in p53 and increased levels of p202 protein in B-cells [20].

Gender differences and markers of increased risk may help predict the likelihood of developing malignancy. A gender bias seems to exist, in which the chance is greater if the first-degree relative with a LPD is either female with lymphoma or male with leukemia [21]. The possibility of malignancy may also be predicted via certain markers. For instance, monoclonal B-cell lymphocytosis (MBL) has been said to exist as a progenitor lesion, or marker of genetic predisposition, for the development of CLL and other B-cell LPD [22]. Whereas MBL occurs in roughly less than 5 percent of those over age 40, in first-degree relatives of CLL patients the rate may be as high as 18 percent [22, 23]. Being mindful that CLL, NHL, and HL tend to cluster in families, this may be significant in practice and the above tenets may be called upon when counseling a patient with a positive family history of LPD.

Pleiotrophy may have a role in familial aggregation of CLL and other B-cell lymphoproliferative disorders [24]. The best elucidation thus far of a single gene locus at 2q21 was completed using a recessive model of CLL in which there was 68 percent familiality [25]. Whereas pleiotrophy may play into familial clustering of B-cell LPD, there seem to be independent factors responsible for each HL and NHL. Some human leukocyte antigen (HLA) haplotypes confer vulnerability to familial forms of HL [10]. The risk of developing NHL has been linked numerous times to polymorphisms in TNF and IL10 [26, 27, 28, 29]. Vulnerability to familial LPD is not likely to involve only one gene locus therefore, but multiple [30]. The association elucidated in these studies does not appear to account for those with positive family histories of LPD who engage in biologic therapy. For instance, one case reports two patients with positive family histories of LPD that subsequently develop malignancy, but makes no mention of TNF inhibitor therapeutics [31].

It is suspected that tumor necrosis factor (TNF) inhibitors increase the risk of malignant lymphoma [32]. TNF inhibitors such as etanercept, infiximab, and adalimumab carry boxed warnings about the increased risk of lymphoma in the package literature [33, 34, 35]. Consequently, TNF inhibitors should be used with consideration of individual risk factors for lymphoma, such as positive family history. Adalimumab and infliximab may heighten the incidence of lymphoma more than etanercept [36]. Few reports link TNF inhibitor therapy with cutaneous lymphoma [37, 38, 39].

The following observations illustrate that family history of lymphoma may not be taken into account in those undergoing TNF inhibitor therapy. A 36-year-old male with a longstanding history of psoriasis developed cutaneous lymphoma after treatment with etanercept. However, a family history of lymphoma was not recorded [40]. Another study compared placebo to etanercept and initially reported about a one-to-one ratio in positive family history of malignancy, including but not limited to lymphoma. At the study’s conclusion, 6 reported cases of solid malignancy were reported, but these were found in the placebo group and not the etanercept treated group [41]. Upon review of psoriatic and other rheumatic disease cases, there are rare instances in which family history of lymphoma is recorded in patients treated with TNF inhibitors [37, 38, 39, 40, 41].

Conclusion

When obtaining family history from a patient, it is recommended that questioning involve the presence of all B-cell malignancies, including CLL. Whereas concern may exist with a positive family history, reassurance can be achieved in that risk is only on the order of about 6 per 100,000 per year [16]. Ravel and Mehta suggest that caution using TNF inhibitors be exercised in treating patients at high-risk of developing cancer [42]. Those with a family history of LPD may fit into this category. In conclusion, immunosuppressant therapy for psoriasis and a positive family history of LPD may increase an already heightened risk of lymphoma in psoriatic patients. Further study regarding this topic may prove beneficial.

References

1. Sivamani RK, Correa G, Ono Y, Bowen MP, Raychaudhuri SP, Maverakis E. Biological therapy of psoriais. Indian J Dermatol 2010 Apr-Jun;55(2):161-70. [PubMed]

2. Tyring S, Gordon KB, Poulin Y, Langley RG, Gottlieb AB, Dunn M, et al. Long-term safety and efficacy of 50 mg of etanercept twice weekly in patients with psoriasis. Arch Dermatol 2007; 143: 719-726. [PubMed]

3. Margolis D, Bilker W, Hennessy S, Vittorio C, Santanna J, Strom BL. The risk of malignancy associated with psoriasis. Arch Dermatol 2001 Jun;137(6):778-83. [PubMed]

4. Gelfand JM, Berlin J, Van Voorhees A, Margolis DJ. Lymphoma rates are low but increased in patients with psoriasis: results from a population-based cohort study in the United Kingdom. Arch Dermatol 2003 Nov;139(11):1425-9. [PubMed]

5. Ferkolj I. How to improve the safety of biologic therapy in Crohn’s disease. J Physiol Pharmacol. 2009 Dec; 60 Suppl 7: 67-70. [PubMed]

6. Razis DV, Diamond HD, Craver LF. Familial Hodgkin’s disease: its significance and implications. Ann Intern Med. 1959 Nov;51:933-71. [PubMed]

7. McDuffie HH, Pahwa P, Karunanayake CP, Spinelli JJ, Dosman JA. Clustering of caner among families of cases with Hodgkin Lymphoma (HL), Multiple Myeloma (MM), Non-Hodgkin’s Lymphoma (NHL), Sofe Tissue Sarcoma (STS) and control subjects. BMC Cancer. 2009 Feb 27;9:70. [PubMed]

8. Chang ET, Smedby KE, Hjalgrim H, et al. Reliability of self-reported family history of cancer in a large case-control study of lymphoma. J Natl Cancer Inst 2006;98:61-8. [PubMed]

9. Linet MS, Pottern LM. Familial aggregation of hematopoietic malignancies and risk of non-Hodgkin’s lymphoma. Cancer Res 1992; 52:5468s-73s. [PubMed]

10. Sonmez M, Erkut N, Ucar F, Buruk K, Cobanoglu U, Bahce M, Ural AU. Familial Hodgkin’s lymphoma from the perspective of HLA. Intern Med. 2010;49(6):607-10. [PubMed]

11. Goldin LR, Pfeiffer RM, Li X, Hemminki K. Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database. Blood. 2004 Sep 15;104(6):1850-4. [PubMed]

12. Brown JR, Neuberg D, Phillips K, Reynolds H, Silverstein J, Clark JC, Ash M, Thompson C, Fisher DC, Jacobson E, LaCasce AS, Freedman AS. Br J Haematol. 2008 Nov;143(3):361-8. [PubMed]

13. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K. Environmental and heritable factors in the causation of cancer - analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000 Jul 13;343(2):78-85. [PubMed]

14. Mensah FK, Willett EV, Ansell P, Adamson PJ, Roman E. Non-Hodgkin’s lymphoma and family history of hematoogic malignancy. Am J Epidemiol 2007; 165(2):126-133. [PubMed]

15. Anderson LA, Pfeiffer RM, Rapkin JS, Gridley G, Mellemkjaer L, Hemminki K, Bjorkholm M, Caporaso NE, Landgren O. Survival patterns among lymphoma patients with a family history of lymphoma. J Clin Oncol 2008 Oct 20; 26(30)4958-65. [PubMed]

16. Slager SL, Kay NE. Familial chronic lymphocytic leukemia: what does it mean to me? Clin Lymphoma Myeloma. 2009;9 Suppl 3:S194-7. [PubMed]

17. Garry VF, Tarone RE, Long L, Griffith J, Kelly JT, Burroughs B. Pesticide appliers with mixed pesticide exposure: G-banded analysis and possible relationship to non-Hodgkin’s lymphoma. Cancer Epidemiol Biomarkers Prev.1996 Jan;5(1):11-6. [PubMed]

18. Landgren O, Engels EA, Pfeiffer RM, Gridley G, Mellemkjaer L, Olsen JH, Kerstann KF, Wheeler W, Hemminki K, Linet MS, Goldin LR. Autoimmunity and susceptibility to Hodgkin lymphoma: a population-based case-control study in Scandinavia. J Natl Cancer Inst 2006 Sep 20;98(18):1321-30. [PubMed]

19. Dias C, Isenberg DA. Susceptibility of patients with rheumatic diseases to B-cell non-Hodgkin lymphoma. Nat Rev Rhematol 2011 Jun;7(6):360-8. [PubMed]

20. Veeranki S, Choubey D. Systemic lupus erythematosus and increased risk to develop B cell malignancies: role of the p200-family proteins. Immunol Lett. 2010 Sep 6;133(1):1-5. [PubMed]

21. Lu Y, Sullivan-Halley J, Cozen W, Chang ET, Henderson K, Ma H, Deapen D, Clarke C, Reynolds P, Neuhausen SL, Anton-Culver H, Ursin G, West D, Berstein L. Family history of haematopoietic malignancies and non-Hodgkin’s lymphoma risk in the California Teacher’s Study. Br J Cancer. 2009 Feb 10;100(3):524-526. [PubMed]

22. Rawstron AC, Green MJ, Kuzmicki A, Kennedy B, Fenton JA, Evans PA, O’Connor SJ, Richards SJ, Morgan GJ, Jack AS, Hillmen P. Monoclonal B lymphocytes with the characteristics of “indolent” chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood. 2002 Jul 15;100(2):635-9. [PubMed]

23. Marti GE, Carter P, Abbasi F, et al. B-cell monoclonal lymphocytosis and B-cell abnormalities in the setting of familial B-cell chronic lymphocytic leukemia. Cytometry B Clin Cytom. 2003; 52(1): 1-12. [PubMed]

24. Crowther-Swanepoel D, Houlston RS. The molecular basis of familial chronic lymphocytic leukemia. Haematologica. 2009 May;94(5):606-9. [PubMed]

25. Sellick GS, Goldin LR, Wild RW, Slager SL, Ressenti L, Strom SS, et al. A high-density SNP genome-wide linkage search of 206 families identifies susceptibility loci for chronic lymphocytic leukemia. Blood. 2007 Nov 1;110(9):3326-33. [PubMed]

26. Lan Q, Zheng T, Rothman N, Zhang Y, Wang SS, Shen M, Berndt SI, Zahm SH, Holford TR, Leaderer B, Yeager M, Welch R, Boyle P, Zhang B, Zou K, Zhu Y, Chanock S. Cytokine polymorphisms in the Th1/Th2 pathway and susceptibility to non-Hodgkin lymphoma. Blood 2006;107:4101-4108. [PubMed]

27. Purdue MP, Lan Q, Kricker A, Grulich AE, Vajdic CM, Turner J, Whitby D, Chanock S, Rothman N, Armstrong BK. Polymorphisms in immune function genes and risk of non-Hodgkin lymphoma: findings from the New South Wales non-Hodgkin Lymphoma Study. Carcinogenesis 2007;28:704-712. [PubMed]

28. Spink CF, Keen LJ, Mensah FK, Law GR, Bidwell JL, Morgan GJ. Association between non-Hodgkin lymphoma and haplotypes in the TNF region. Br J Haematol 2006;133:293-300. [PubMed]

29. Wang SS, Cerhan JR, Hartge P, Davis S, Cozen W, Severson RK, Chatterjee N, Yeager M, Chanock SJ, Rothman N. Common genetic variants in proinflammatory and other immunoregulatory genes and risk for non-Hodgkin lymphoma. Cancer Res 2006;66:9771-9780. [PubMed]

30. Liang XS, Caporaso N, McMaster ML, Ng D, Landgren O, Yeager M, Chanock S, Goldin LR. Common genetic variants in candidate genes and risk of familial lymphoid malignancies. Br J Haematol. 2009 Aug;146(4):418-23. [PubMed]

31. Touma Z, Kibbi L, Arayssi T. Family history of lymphoma and risk for solid tumors in patients with Sjogren’s syndrome. Rheumatol Int. 2007 Nov;28(1):87-88. [PubMed]

32. Theophile H, Schaeverbeke T, Miremont-Salame G, Abouelfath A, Kahn V, Haramburu F, Begaud B. Sources of information on lymphoma associated with anti-tumour necrosis factor agents: comparison of published case reports and cases reported to the French phamcovigilance system. Drug Saf. 2011 Jul 1;34(7):577-85. [PubMed]

33. Abbott Laboratories. Humira® (adalimumab) package insert; 2006. Chicago, IL, USA.

34. Immunex Corporation. Enbrel® (etanercept) package insert; 2005. Thousand Oaks, CA, USA.

35. Centocor Inc. Remicade® (infliximab) package insert; 2005. Malvern, PA, USA.

36. Mariette X, Tubach F, Bagheri H, Bardet M. Lymphoma in patients treated with anti-TNF: results of the three-year prospective French RATIO registry. Ann Rheum Dis 2010 Feb; 69(2)400-8.

37. Adams AE, Zwicker J, Curiel C, Kadin ME, Falchuk KR, Drews R, et al. Aggressive cutaneous T-cell lymphomas after TNFalpha blockade. J Am Acad Dermatol 2004; 51: 660-662. [PubMed]

38. Berthelot C, Cather J, Jones D, Duvic M. Atypical CD8+ cutaneous T-cell lymphoma after immunomodulatory therapy. Clin Lymphoma Myeloma 2006; 6: 329-332. [PubMed]

39. Dalle S, Balme B, Berger F, Hayette S, Thomas L. Mycosis fungoides-associated follicular mucinosis under adalimumab. Br J Dermatol 2005; 153: 207-208. [PubMed]

40. Quereux G, Renaut JJ, Peuvrel L, Knol AC, Bocard A, Dreno B. Sudden onset of an aggressive cutaneous lymphoma in a young patient with psoriasis: role of immunosuppressants. Acta Derm Venereol. 2010 Nov;90(6):616-20. [PubMed]

41. Stone JH, Holbrook JT, Marriott MA, Tibbs AK, Sejismundo LP, Min YI, Specks U, Merkel PA, Spiera R, Davis JC, St Clair EW, McCune WJ, Ytterberg SR, Allen NB, Hoffman GS, Wegener’s Granulomatosis Etanercept Trial Research Group. Solid malignancies among patients in the Wegener’s Granulomatosis Etanercept Trial. Arthritis Rheum. 2006 May;54(5):1608-18. [PubMed]

42. Ravel G, Mehta P. TNF-alpha inhibitors: are they carcinogenic? Drug Healthc Patient Saf. 2010;2:241-247. [PubMed]

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