Skip to main content
eScholarship
Open Access Publications from the University of California

Sustained effects of low dose infliximab in combination with methotrexate in the management of chronic recalcitrant psoriasis

  • Author(s): Zargari, Omid
  • et al.
Main Content

Sustained effects of low dose infliximab in combination with methotrexate in the management of chronic recalcitrant psoriasis
Omid Zargari MD
Dermatology Online Journal (11) 3: 21

Assistant Professor of Dermatology, Department of Dermatology, Guilan University of Medical Sciences, Rasht, Iran. ozargari@iranderma.com

Abstract

Psoriasis is a chronic inflammatory skin disease whose pathogenesis is modulated by numerous genetic and immunologic factors. During the last decade, our understanding of the pathophysiology of psoriasis has significantly improved, and the disease is now accepted as a T-cell mediated process. This concept has dramatically altered the approach to the treatment of psoriasis. Tumor necrosis factor-α (TNF-α) is one of the key chemokines in the pathophysiology of psoriasis and its expression is notably increased in psoriatic plaques. Infliximab is a chimeric anti-TNF-α monoclonal antibody that binds to both transmembrane and soluble TNF-α with high affinity, specificity, and avidity. Presented here is a severe recalcitrant case of psoriasis with sustained benefit from low-dose infliximab in combination with methotrexate.



Clinical synopsis


Figure 1A Figure 1B

Figure 1C
Improvement of psoriasis during treatment with infliximab: A. Before treatment, B. Week 2, C. Week 6.

A 28-year-old woman with no family history of psoriasis was referred with a 15-year history of severe plaque-type psoriasis. Her disease initially began on her elbows and progressed to involve her trunk, scalp, and face. She also developed progressive non-destructive arthropathy in the small joints of her hands and feet. Her disease was relatively stable until 2 years prior to referral, when she became pregnant with her first child. After delivery, her lesions rapidly progressed to affect most of her skin with periods of erythroderma.

During the previous 13 years, she had received a variety of topical and systemic therapies. She had received methotrexate (MTX) intermittently during the previous 8 years, with an average dose of 10-15 mg per week. The total cumulative dose of MTX was greater than 2 grams, but the patient adamantly refused a liver biopsy. She had also received systemic retinoids in the form of acitretin 4 years ago. She subsequently underwent PUVA therapy with a maximum dose of 11.5 J/cm² and total cumulative dose of 812.25 J/cm² in 114 sessions.

During the previous 6 months, her lesions stopped responding to PUVA and new lesions developed progressively. Furthermore, she developed extensive PUVA lentigines, raising concerns about the development of cutaneous malignancy and making the patient more reluctant to continue with phototherapy. Because of poor response to retinoids, MTX, and PUVA, and because of worsening arthropathy, a change in therapy was both necessary and demanded by the patient. Because of the history of long term PUVA therapy, we were reluctant to use cyclosporine. Therefore, after informing the patient about the risks and benefits of new biological therapies for psoriasis and the available alternative therapies, she was placed on infliximab.


Management

The patient was admitted to our department (Razi hospital, Rasht, Iran). At the time of admission, more than 50 percent of her skin surface was involved with psoriasis and there was swelling, tenderness, and decreased range of motion in proximal interphalangeal (PIP) joints of both upper and lower extremities. Her PASI (Psoriasis Area and Severity Index) score was 30.0 and she was receiving oral methotrexate 10 mg/week, prednisolone 7.5 mg/day, sulfasalazine 2gr/day and celecoxib 200 mg/day. Her basic biochemical examinations were in the normal range. PPD (purified protein derivative of tuberculin) test was negative and chest X-ray was normal. She refused skin biopsy.

After admission, all medications except prednisolone and oral methotrexate were discontinued and infliximab (Remicade, Centocor, Malvern, Pa) was initiated with a dose of 300 mg (3mg/kg) infused intravenously over 4 hours. By 48 hours the patient noted improvement in joint pain. Her cutaneous psoriasis responded dramatically during next several days. At week 2, the patient had achieved a significant improvement with a PASI score of 10.5. The improvement in the joint and cutaneous disease activity allowed us to taper off both the prednisolone and MTX. At week 6, the patient had 90 percent improvement and her PASI dropped to 3.0 (Fig. 1). At that time, a second dose of infliximab with the same dose was infused. The patient tolerated the therapy without any infusion reactions or adverse effects; her blood count, liver enzyme levels, and renal function remained normal throughout treatment.

The patient was very satisfied by the treatment and had a sustained remission. Sixteen weeks following the first infusion, only traces of disease remained on the knees and buttocks, but she was still suffering from arthralgias. At this point, the patient finally agreed to undergo a liver biopsy, which showed macrovesicular fatty changes compatible with mild to moderate steatohepatitis with no evidence of fibrosis. We therefore resumed methotrexate at a dose of 0.2 mg/kg intramuscularly each week. This maintained her cutaneous remission, but because of relapse of her arthritis, infliximab (3 mg/kg) was infused at week 24.


Discussion

Phototherapy, systemic retinoids, methotrexate and cyclosporine are the four major therapies in moderate-to-severe psoriasis, but in clinical practice monotherapy with these agents often fails to induce a sustained remission in patients with severe forms of psoriasis. The use of combination therapy, rotational therapy and sequential therapy can reduce the cumulative dose of these drugs. Furthermore, certain combinations of treatment are synergistic, with combined effectiveness or safety profiles better than that of each agent alone [1].

During the last decade, a better understanding of psoriasis has been achieved and it is now known that psoriasis is a T-cell mediated disease. Tumor necrosis factor-α (TNF-α) plays a central role in the pathogenesis of psoriasis and its expression is notably increased in both serum and skin lesions of psoriatic patients [2]. Infliximab is a mouse/human chimeric anti-TNF-α monoclonal antibody (IgG1) that binds to both transmembrane-bound and soluble TNF-α with high specificity, affinity, and avidity [3]; several studies have confirmed the efficacy and safety of infliximab monotherapy in treatment of psoriasis [4, 5, 6].

Gottlieb et al. demonstrated that there is no significant difference between 5 and 10 mg/kg of infliximab in inducing significant clearing of disease, although it appears that the duration of remission is dose-related and in general is about 14 weeks for the 5 mg/kg dose as compared with 18 weeks for those receiving 10 mg/kg [7].

Our patient received infliximab at lower than recommended doses. Also, because of financial constraints and given the dramatic and sustained response and patient satisfaction, we used infliximab at weeks 0 and 6 despite recommended infusions at 0, 2, and 6 weeks. Our patient had a rapid, dramatic and sustained response to infliximab and this is in accordance with recent reports that have demonstrated the clear clinical and histopathological improvement with infliximab seen within 2 weeks of therapy [8, 9].

Because infliximab is not hepatotoxic and does not affect bone marrow cell proliferation, it is probably safe to use it in combination with MTX; no drug interactions have been noted in clinical trials when infliximab was administered concurrently with MTX [9]. Clinically this combination has been evaluated in rheumatoid arthritis [10]. Furthermore, it appears that infliximab loses its effect and is associated with more neutralizing antibodies in the absence of a concomitant immunosuppressive agent [11]. Therefore, it appears that using a second immunosuppressive agent in combination with infliximab may prevent the formation of neutralizing antibodies and help maintain the efficacy of infliximab. Based on these data we used MTX as both a sequential and concomitant therapy in our patient and found the combination both safe and effective in this patient.

Given the mechanism of action of infliximab, the risk of infections, particularly tuberculosis, must be considered in patients receiving this biologics. Keane et al. reported the development of tuberculosis in 70 patients out of approximately 147,000 patients treated with infliximab [12], but this risk would be higher in areas with a higher prevalence of tuberculosis. As such, testing for dormant tuberculosis is strongly recommended, if not mandatory, before initiating therapy.

In summary, we observed a beneficial effect of low dose infliximab for recalcitrant psoriasis and we suggest that even low dose infliximab infusions with longer intervals may be effective in inducing remission in patients with severe recalcitrant psoriasis. Also we suggest that in such forms of psoriasis, infliximab can be used as a rapid remission inducer followed by administration of MTX for maintenance therapy and prevention of antibody formation against infliximab. Certainly, with regard to the possibility of reactivation of tuberculosis by infliximab, multicenter trials are necessary to confirm the safety of this medication in areas with a high prevalence of latent tuberculosis.

References

1. Lebwohl M, Menter A, Koo J, Feldman SR. Combination therapy to treat moderate to severe psoriasis. J Am Acad Dermatol 2004;50:416-30

2. Ettehadi P, Greaves MW, Wallach D, Aderka D, Camp RDR. Elevated tumor necrosis factor-alpha biological activity in psoriatic skin lesions. Clin Exp Immunol 1994;96:146-51

3. Scallon BJ, Moore MA, Trinh H, Knight DM, Ghrayeb J. Chimeric anti-TNF-alpha monoclonal anti-body cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 1995;7:251-9

4. Oh CJ, Das KM, Gottlieb AB. Treatment with anti-tumor necrosis factor α (TNF- α) monoclonal antibody dramatically decreases the clinical activity of psoriasis lesions. J Am Acad Dermatol 2000;42:829-30

5. Chaudhari U, Romano P, Mulcahy L, Dooley L, Baker D, Gottlieb A. efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomized trial. Lancet 2001;357:1842-7

6. Schopf RE, Aust H, Knop J. Treatment of psoriasis with the chimeric monoclonal antibody against tumor necrosis factor α, infliximab. J Am Acad Dermatol 2002;46:886-91

7. Gottlieb AB, Chaudhari U, Mulcahy L, Li S, Dooley L, Baker D. Infliximab monotherapy provides rapid and sustained benefit for plaque-type psoriasis. J Am Acad Dermatol 2003;48:829-35

8. Vincek V, Jacob SE, Nassiri M, Herbert LM, Nadji M, Kerdel FA. Infliximab monotherapy in psoriasis: A case of rapid clinical and histological response. Int J Dermatol 2004;43:303-8

9. Gottlieb AB. Infliximab for psoriasis. J Am Acad Dermatol 2003;49:S112-17

10. Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis: anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study group. N Engl J Med 2000;343:1594-602

11. Baert F, Noman M, Vermeire S, Van Assche G, DÕ Haens G, Carbonez A, et al. Influence of immunogenicity on the long-term efficacy of infliximab in CrhonÕs disease. N Engl J Med 2003;348:601-8

12. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098-104

© 2005 Dermatology Online Journal