To determine whether there is an association between the use of immunosuppressive agents (ISAs) and cancer in patients with pemphigus and pemphigoid—rare, potentially fatal diseases of the skin and mucous membranes, often requiring long-term use of ISAs.
Data Source:
Literature was accessed through PubMed (all years available), using the search terms cancer, immunosuppressive agents, pemphigoid, and pemphigus.
Study Selection and Data Extraction:
A retrospective review of the literature was conducted. Inclusion criteria for studies were: (1) English language, (2) diagnosis of pemphigus and/or pemphigoid based on histology and immunopathology, (3) more than 10 patients evaluated, (4) investigators had a high index of suspicion of cancer and patients were monitored for it, (5) follow-up information was provided for at least 1 year after initiation of therapy, and (6) absence of diagnosis of cancer before initiation of an ISA. Case reports were not included in the analysis.
Data Synthesis:
A total of 929 patients diagnosed with either pemphigus or pemphigoid in 17 studies were identified. Patients were divided into 2 groups. Group A comprised patients treated with azathioprine, cyclophosphamide, cyclosporins, or mycophenolate mofetil in combination with prednisone. In Group A. 22 cases of cancer were reported in 21 of the 218 patients (9.6%). Group B comprised patients treated with systemic corticosteroids only. In this group, cancer was reported in 11 of the 711 patients (1.5%). In this study there was no control group (untreated patients) and the sample sizes were small.
Conclusions:
Preliminary data suggest a possible association between the use of azathioprine, cyclophosphamide, and cyclosporine and increased susceptibility to cancer in patients with pemphigus and pemphigoid.
ZillikensD. Diagnosis of autoimmune bullous skin diseases. Clin Lab2008; 54:491–503.
2.
AhmedAR. Recent advances in the treatment of autoimmune mucocutaneous blistering diseases. Int J Periodontics Restorative Dent2007; 27:309–10.
3.
KormanNJ. New immunomodulating drugs in autoimmune blistering diseases. Dermatol Clin2001; 19:637–48.
4.
AhmedAR, ChuTM, ProvostTT. Bullous pemphigoid: clinical and serologic evaluation for associated malignant neoplasms. Arch Dermatol1977; 113:96–9.
5.
HennekensCH, BuringJE. Epidemiology in medicine. Boston: Little, Brown and Company, 1987.
6.
ThorneJE, WoretaFA, JabsDA, AnhaltGJ. Treatment of ocular mucous membrane pemphigoid with immunosuppressive drug therapy. Ophthalmology2008; 115:2146–52
7.
PowellAM, AlbertS, Al FaresS. An evaluation of the usefulness of mycophenolate mofetil in pemphigus. Br J Dermatol2003; 149:138–45.
8.
OlszewskaM, Kolacinska-StraszZ, SulejJ. Efficacy and safety of cyclophosphamide, azathioprine, and cyclosporine as adjuvant drugs in pemphigus vulgaris. Am J Clin Dermatol2007; 8:85–92.
9.
CumminsDL, AnhaltGJ, MonahanT, MeyerleJH. Oral cyclophosphamide for treatment of pemphigus vulgaris and foliaceus. J Am Acad Dermatol2003; 49:276–80.
10.
AbererW, Wolff-SchreinerEC, StinglG, WolffK. Azathioprine in the treatment of pemphigus vulgaris. A long-term follow-up. J Am Acad Dermatol1987; 16:527–33.
11.
LameyPJ, ReesTD, BinnieWH. Oral presentation of pemphigus vulgaris and its response to systemic steroid therapy. Oral Surg Oral Med Oral Pathol1992; 74:54–7.
12.
LintonWT, CraigGE. Pemphigus: a comparison of the results of treatment at the Royal Victoria Hospital, Montreal, in the steroid and presteroid eras. Can Med Assoc J1961; 85:1192–4.
13.
MashkilleysonN, MashkilleysonAL. Mucous membrane manifestations of pemphigus vulgaris. A 25-year survey of 185 patients treated with corticosteroids or with combination of corticosteroids with methotrexate and heparin. Acta Derm Venereol1988; 68:413–21.
14.
FernandesNC, PerezM. Treatment of pemphigus vulgaris and pemphigus folliaceus: experience with 71 patients over a 20-year period. Rev Inst Med Trop S Paulo2001; 43:33–6.
15.
LeverWF, WhiteH. Treatment of pemphigus with corticosteroids: results obtained in 46 patients over a period of 11 years. Arch Dermatol1963; 87:12–26.
16.
RosenbergFR, SandersS, NelsonCT. Pemphigus: a 20-year review of 107 patients treated with corticosteroids. Arch Dermatol1976; 112:962–70.
17.
CostelloMJ, JaimovichL, DannenbergM. Treatment of pemphigus with corticosteroids; study of fifty-two patients. JAMA1957; 165:1249–55.
18.
SandersSL, BrodeyM, NelsonCT. Corticosteroid treatment of pemphigus. Experience with fifty cases over a period of ten years. Arch Dermatol1960; 82:717–24.
19.
ChurchR. Pemphigoid treated with corticosteroids. Br J Dermatol1960; 72:434–8.
20.
NelsonCT, BrodeyM. Cortisone and corticotropin treatment of pemphigus; experience with twenty-eight cases over a period of five years. AMA Arch Derm1955; 72:495–505.
TerhorstD, DrecollU, StockflethEl, UlrichC. Organ transplant recipients and skin cancer: assessment of risk factors with focus on sun exposure. Br J Dermatol2009; 161:85–9.
26.
LanoyE, CostagliolaD, EngelsEA. Skin cancers associated with HIV infection and solid organ transplant among elderly adults. Int J Cancer2010; 126:1724–31.
27.
EganCA, LazarovaZ, DarlingTN. Anti-epiligrin cicatricial pemphigoid and relative risk for cancer. Lancet2001; 357:1850–1.
28.
EganCA, LazarovaZ, DarlingTN. Anti-epiligrin cicatricial pemphigoid: clinical findings, immunopathogenesis, and significant associations. Medicine (Baltimore)2003; 82:177–86.
29.
MalikM, GürcanHM, ChristenW, AhmedAR. Relationship between cancer and oral pemphigoid patients with antibodies to alpha6-integrin. J Oral Pathol Med2007; 36:1–5.
30.
LetkoE, GürcanHM, PapaliodisGN. Relative risk for cancer in mucous membrane pemphigoid associated with antibodies to the beta4 integrin subunit. Clin Exp Dermatol2007; 32:637–41.
MarcilI, SternRS. Squamous-cell cancer of the skin in patients given PUVA and ciclosporin: nested cohort crossover study. Lancet2001; 358:1042–5.
33.
KooJY, KadonagaJN, WintroubBV, Lozada-NurFI. The development of β-cell lymphoma in a patient with psoriasis treated with cyclosporine. J Am Acad Dermatol1992; 26:836–40.
34.
WatabeH, SomaY, ObaraW. Adult T-cell lymphoma/leukaemia developing in a patient with psoriasis treated with long-term cyclosporine. Acta Derm Venereol2006; 86:184–5.
35.
LelièvreJD, SacreK, Adle-BiassetteH. Epstein-Barr virus-associated lymphoproliferative disease after long-standing cyclosporine therapy for psoriasis: a case of spontaneous regression. J Am Acad Dermatol2005; 52:24–7.
36.
LainEL, MarkusRF. Early and explosive development of nodular basal cell carcinoma and multiple keratoacanthomas in psoriasis patients treated with cyclosporine. J Drugs Dermatol2004; 3:680–2.
37.
CorazzaM, ZampinoMR, MontanariA. Primary cutaneous CD30+ large T-cell lymphoma in a patient with psoriasis treated with cyclosporine. Dermatology2003; 206:330–3.
38.
MahéE, DescampsV, GrossinM. CD30+ T-cell lymphoma in a patient with psoriasis treated with ciclosporin and infliximab. Br J Dermatol2003; 149:170–3.
39.
FozzaC, DoreF, BonfigliS. Two cases of chronic lymphoproliferative disorders in psoriatic patients treated with cyclosporine: hairy cell leukemia and waldenstrom macroglobulinemia. Eur J Dermatol2005; 15:271–3.
40.
BehnamSM, BehnamSE, KooJY. Review of cyclosporine immunosuppressive safety data in dermatology patients after two decades of use. J Drugs Dermatol2005; 4:189–94.
41.
ZachariaeH, KragballeK, HansenHE. Renal biopsy findings in long-term cyclosporin treatment of psoriasis. Br J Dermatol1997; 136:531–5.
42.
PaulCF, HoVC, McGeownC. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study. J Invest Dermatol2003; 120:211–6.
43.
LynchWS, RoenigkHHJr. Mycophenolic acid for psoriasis. Arch Dermatol1977; 113:1203–8.
44.
EpinetteWW, ParkerCM, JonesEL, GreistMC. Mycophenolic acid for psoriasis. A review of pharmacology, long-term efficacy, and safety. J Am Acad Dermatol1987; 17:962–71.
45.
SilmanAJ, PetrieJ, HazlemanB, EvansSJ. Lymphoproliferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine: a 20 year follow up study. Ann Rheum Dis1988; 47:988–92.
46.
RadisCD, KahlLE, BakerGL. Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis. A 20-year followup study. Arthritis Rheum1995; 38:1120–7.
47.
BaltusJA, BoersmaJW, HartmanAP, VandenbrouckeJP. The occurrence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide: a controlled retrospective follow-up. Ann Rheum Dis1983; 42:368–73.
48.
AstenP, BarrettJ, SymmonsD. Risk of developing certain malignancies is related to duration of immunosuppressive drug exposure in patients with rheumatic diseases. J Rheumatol1999; 26:1705–14.
49.
KeysserG, KeysserC, KeysserM. Treatment of refractory rheumatoid arthritis with low dose cyclophosphamide. Long term follow-up of 108 patients. Z Rheumatol1998; 57:101–7.
50.
BuchbinderR, BarberM, HeuzenroederL. Incidence of melanoma and other malignancies among rheumatoid arthritis patients treated with methotrexate. Arthritis Rheum2008; 59:794–9.
51.
BernatskyS, ClarkeAE, SuissaS. Hematologic malignant neoplasms after drug exposure in rheumatoid arthritis. Arch Intern Med2008; 168:378–81.
52.
RawootA, LittleF, HeckmannJM. Risk of malignancy in myasthenia gravis patients exposed to azathioprine therapy for a median period of 3 years. S Afr Med J2006; 96:1249–51.
53.
HohlfeldR, MichelsM, HeiningerK, BesingerU. Azathioprine toxicity during long-term immunosuppression of generalized myasthenia gravis. Neurology1988; 38:258–61.
54.
PutzkiN, KnippS, RamczykowskiT. Secondary myelodysplastic syndrome following long-term treatment with azathioprine in patients with multiple sclerosis. Mult Scler2006; 12:363–6.
55.
ConfavreuxC, SaddierP, GrimaudJ. Risk of cancer from azathioprine therapy in multiple sclerosis: a case–control study. Neurology1996; 46:1607–12.
