In Treating Recalcitrant Psoriasis a Report of 2 Cases

OBSERVATION The Effectiveness of Tumor Necrosis Factor ␣ Antibody (Infliximab) in Treating Recalcitrant Psoriasis A Report of 2 Cases

Ryan P. O’Quinn, MD; Jami L. Miller, MD

Background: Psoriasis is being recognized as an auto- liximab. The treatments resulted in rapid and complete immune disease in which immunocyte-derived cyto- clearing of psoriatic erythroderma and resolution of symp- kines are thought to drive the development of the al- toms of arthritis in one case and complete clearing of wide- tered keratinocyte phenotype. Although the role of tumor spread psoriatic plaques and improvement of symptoms necrosis factor ␣ (TNF-␣) in psoriasis is not completely of arthritis and inflammatory bowel disease in the other. understood, it may underlie many of the key steps that The single treatments with infliximab were well tolerated lead to induction and maintenance of the disease. In- with no immediate or long-term adverse effects noted. fliximab is an immunoglobulin monoclonal antibody that binds and inactivates TNF-␣ and has been successfully Conclusion: A single infusion of infliximab at 5 to 10 used in the management of TNF-␣–mediated diseases, mg/kg resulted in the rapid and complete clearing of re- such as Crohn disease and rheumatoid arthritis. calcitrant psoriatic plaques and erythroderma with a disease-free interval of 3 to 4 months in these 2 patients and Observations: Two patients with recalcitrant psoriasis improved the symptoms of psoriatic arthritis. that was unresponsive to multiple skin-directed and systemic therapies were treated with a single infusion of inf- Arch Dermatol. 2002;138:644-648

NHIBITION OF tumor necrosis fac- ment with oral etretinate, 50 mg/d, com- tor ␣ (TNF-␣) has been shown to bined with psoralen–UV-A initially showed improve psoriasis and psoriatic significant clearing but had to be discon- arthritis. The following case re- tinued owing to unmanageable hyper- ports detail our experience us- triglyceridemia. Acetretin use also was ingI the TNF-␣ antibody infliximab. discontinued because of high serum tri- glyceride levels. Treatment with 6-thiogua- REPORT OF CASES nine resulted in lowered hematocrit and white blood cell count and was stopped. CASE 1 Other treatments that failed to clear the psoriasis included up to 25 mg/wk of metho- A 52-year-old white man presented with trexate administered by both the oral and a 17-year history of widespread recalci- intramuscular routes, up to 6 mg/kg daily trant psoriasis vulgaris. He initially had of cyclosporine, 150 mg/d of azathio- well-defined psoriatic plaques with adher- prine, and 200 mg/d of hydroxyurea. ent silvery scale that slowly spread de- The patient was seen in March 2000 spite treatment and coalesced to cover most with worsening arthritis in the back and of the skin surface. Except for sparing of fingers and psoriatic erythroderma. At this the face and dorsal aspects of the hands, time, the patient was using only topical tri- he had had erythroderma for the past 7 amcinolone acetonide ointment. He com- years. In addition, the patient com- plained of intense itching and occasional plained of nail involvement and psoriatic chills, but denied fever or sweats. On arthritis of the distal interphalangeal and physical examination, the patient had thick sacroiliac joints. erythematous plaques with scale cover- From the Department of Multiple topical and systemic thera- ing more than 85% of the skin surface Medicine, Division of pies failed to arrest the development of (Figure 1). There were islands of spar- Dermatology, Vanderbilt erythroderma. Topical steroids and calci- ing on the face and dorsal aspects of the University, Nashville, Tenn. potriene were used without effect. Treat- hands. The nails were pitted with subun-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Figure 3. Skin biopsy results from the arm of patient 1 before infliximab treatment. Note typical histological findings for psoriasis (hematoxylin-eosin, original magnification ϫ200). Figure 1. Patient 1 before infusion of infliximab.

Figure 4. Skin biopsy results from the arm of patient 1, eight weeks after a single infusion of infliximab. Note normalization of histologic findings Figure 2. Patient 1 eight weeks after a single infusion of infliximab. (hematoxylin-eosin, original magnification ϫ200).

gual hyperkeratosis. The distal interphalangeal joints arm 10 days after treatment with infliximab revealed a showed some edema and pain with active motion. resolution of psoriasiform epidermal changes. The stra- After informed consent was obtained, 10 mg/kg of tum corneum showed an orthokeratotic basket weave pat- infliximab (Remicade; Centocor, Malvern, Pa) was ad- tern, whereas the epidermis showed spongiosis with a mild ministered intravenously over 3 hours after premedica- perivascular lymphocytic infiltrate and occasional eo- tion with acetaminophen and diphenhydramine hydro- sinophils (Figure 4). chloride. No adverse effects were associated with the The patient noted the onset of slight pruritus infusion. Within 2 days the patient noted a decrease in beginning 4 weeks after treatment, which he thought pruritus and erythema of the skin and resolution of his heralded the onset of new psoriatic skin involvement. chills and cold intolerance. A follow-up examination 10 Follow-up after 8 weeks showed a few small erythema- days after the infusion showed that the plaques were no- tous plaques on the legs, but the patient’s trunk, arms, ticeably thinner to palpation. Significant improvement and scalp remained clear. Ongoing treatment with in the erythema with persistence of scaling was noted. sunlight exposure and topical triamcinolone was The patient reported resolution of pain associated in the instituted. The patient relapsed with development of distal interphalangeal and sacroiliac joints, and the re- psoriatic plaques 3 months following treatment. sults of the clinical examination of the fingers were clinically normal, with no pain on active motion. CASE 2 A 4-week follow-up examination showed complete resolution of all psoriatic plaques, erythema, and A 33-year-old white woman presented with an 8-year his- scaling (Figure 2). The patient’s skin was clinically tory of psoriasis vulgaris and psoriatic arthritis. She ini- normal for the first time in 7 years. tially presented with confluent scale over the entire scalp A biopsy specimen of the left forearm was taken be- and generalized erythematous plaques with adherent sil- fore treatment with infliximab, which showed psoriasi- very scale measuring 0.5 to 6.0 cm2 over the chest, ab- form acanthosis of the epidermis with parakeratosis of domen, back, buttocks, gluteal crease, and upper and the stratum corneum, infiltrating neutrophils forming lower extremities. She also had edema, warmth, and nearly Munro microabscesses, thinning of the suprapapillary incapacitating pain in the phalangeal joints. Her medi- plates, and dilated blood vessels in the dermal papillae cal history was also notable for diarrhea, hematochezia, (Figure 3). A follow-up biopsy specimen of the left fore- and crampy abdominal pain diagnosed by upper and lower

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 psoriatic plaques within 24 hours. She also noted a rapid resolution of diarrhea and abdominal symptoms. Com- plete clearing of the plaques occurred within 2 weeks, and arthritis symptoms improved significantly. A follow-up examination after 2 weeks was remarkable for complete clearing of all plaques with residual macules and patches of hyperpigmentation with minimal over- lying scale (Figure 5). Examination of the interphalangeal joints showed no erythema and minimal discom- fort on active motion. Biweekly etanercept, 25 mg subcutaneously, was initiated. The patient discontinued the etanercept therapy after 2 weeks. She main- tained a 4-month disease-free interval before relapsing with psoriatic plaques and arthritis.

Figure 5. Patient 2 one month after a single dose of infliximab. Note flat, mostly hyperpigmented lesions. COMMENT

Tumor necrosis factor ␣ is a cytokine that induces pro- gastrointestinal tract endoscopy as unspecified inflam- inflammatory effects by binding to specific TNF recep- matory bowel disease. tors and activating the NF-␬B signal transduction path- Multiple therapeutic regimens were administered that way.1 As a primary cytokine, it can evoke all the steps ultimately failed to produce significant clearing and con- required to produce immunocyte infiltration in tissues, trol of the patient’s psoriatic plaques and arthritis. A pre- including the up-regulation of cell adhesion molecule ex- vious trial of psoralen–UV-A had been terminated because pression and the induction of secondary cytokines and of psoralen intolerance. Treatment with high-potency topi- chemokines.2 Primarily secreted by macrophages, mono- cal steroids, topical calcipotriene, and methotrexate was cytes, and T cells, newly synthesized TNF-␣ is a cell sur- begun. The methotrexate dose was increased up to 15 mg/ face transmembrane protein before its release as a soluble wk to a total dose of 290 mg. Despite some improvement protein homotrimer.3 of both skin and joint disease, its use was discontinued Psoriasis is being recognized as an autoimmune dis- because of the onset of diarrhea. A trial of topical tazaro- ease. Immunocyte-derived cytokines are thought to me- tene was ineffective. Broad-band UV-B for 12 treatments diate the altered keratinocyte phenotype.4 The cytokine 5,6 ␣ followed by narrow-band UV-B for 43 treatments was given. profile derives from the TH1 subset. Accordingly, TNF- Many plaques decreased in size but were still present, and has been shown to be overexpressed in psoriatic skin le- the psoriatic arthritis worsened. Treatment with cyclospor- sions and in the synovium and synovial fluid in patients ine, 4 mg/kg, showed improvement in both skin and joint with psoriatic arthritis.7-9 The role of the cytokine TNF-␣ symptoms, but its use was soon discontinued because of in psoriasis is incompletely understood, but it may un- intractable headaches. Azathioprine therapy was begun derlie many of the steps that lead to induction and pro- concurrently with cyclosporine therapy and titrated up gression of the disease. The most important function of to 100 mg/d. After 3 months, no response was noted. TNF-␣ may be the initiation of a proinflammatory cyto- In January 2000, the patient presented with low- kine cascade that leads to the recruitment of leukocytes grade fever (temperature, 37.8°C) and complaints of wors- to lesional epidermis. Several observations point to such ening joint pain and swelling, increased numbers of pso- a role. In psoriasis, endothelial cells express TNF-␣– riatic plaques, and bloody diarrhea accompanied by regulated adhesion molecules, such as intercellular ad- crampy abdominal pain. Physical examination findings hesion molecule 1 and E-selectin, that are critical for the were notable for erythematous, thin, guttate plaques and migration of activated leukocytes into areas of inflam- papules over the arms, legs, back, chest, and abdomen. mation.10 Adhesion molecules have also been noted on There were scaling patches on the scalp. The distal and psoriatic keratinocytes.11-13 In addition, increased con- proximal interphalangeal joints were erythematous, centrations of TNF-␣ have been found in the serum in edematous, and tender. The patient, although moti- generalized pustular psoriasis.14,15 Attention has re- vated and compliant with therapy, had had a poor re- cently been focused on promoter region polymor- sponse to conventional topical treatment, photo- phisms of the TNF-α gene in patients with psoriasis.16,17 therapy, and systemic immunosuppressive agents. In Inhibition of TNF-␣ has been shown to improve pso- addition, intolerance to multiple agents and the poten- riasis and psoriatic arthritis. A recent randomized con- tial to exacerbate the inflammatory bowel disease lim- trolled study18 showed that a 25-mg twice-weekly dose ited treatment options. An alternate treatment to ad- of the TNF-␣ inhibitor etanercept provided a statisti- dress both the refractory psoriasis and inflammatory bowel cally significant clinical benefit in disease activity of pso- disease was needed. riatic skin lesions and psoriatic arthritis. After informed consent was obtained, infliximab was Infliximab is a chimeric (murine-human) immu- administered intravenously at a dosage of 5 mg/kg for 3 noglobulin monoclonal antibody that was developed to hours. The patient was premedicated with acetamino- treat TNF-␣–mediated diseases.19 It binds soluble phen and diphenhydramine, and the infusion was toler- TNF-␣ with high affinity and specificity and neutralizes ated well. The patient reported decreased erythema in the its effects by preventing it from binding with the TNF

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 receptors. It has been shown in vitro that infliximab flammatory bowel disease and may be of use in patients also interacts with membrane-bound TNF-␣, leading to in whom these diseases coexist.34 Use of infliximab should lysis of the cell.20 be reserved for those patients who are acutely ill and in Infliximab has been used with success in multiple whom more conventional therapies have failed. It may trials in the treatment of Crohn disease and rheumatoid be a useful agent in such patients to rapidly clear wide- arthritis; both are diseases in which TNF-␣ plays a cen- spread psoriasis before other systemic and skin- tral role in the pathogenesis.21-23 Treatment with inflix- directed therapies begin to mediate their effects. The role imab has led to observations of profound down- of infliximab in TNF-␣–mediated diseases seems very regulation of inflammation in Crohn disease and promising. The efficacy of a treatment suggested by a rheumatoid arthritis. In Crohn disease, a regression of single report may serve to provide clues about the patho- the inflammatory infiltrate, especially neutrophils, is genesis of a disease, but will need to be subjected to tri- noted, as well as a reduction or disappearance of activa- als before its widespread use. tion markers and adhesion molecules such as aberrant HLA-DR expression, intercellular adhesion molecule 1, Accepted for publication August 20, 2001. and leukocyte function–associated antigen 1.24 Similar Corresponding author and reprints: Jami L. Miller, MD, findings have been observed in patients with rheuma- 3900 The Vanderbilt Clinic, Nashville, TN 37232 (e-mail: toid arthritis treated with the antibody.25,26 Infliximab also [email protected]). suppresses serum markers of inflammation, such as C- reactive protein and the erythrocyte sedimentation rate, REFERENCES and down-regulates the production of numerous cytokines in vivo.26,27 In addition, some actions of inflix- 1. Barnes PJ, Karin M. Nuclear factor-␬B: a pivotal transcription factor in chronic imab may be due to an inhibition of angiogenesis that inflammatory diseases. N Engl J Med. 1997;336:1066-1067. 26 2. Kupper TS. Immune and inflammatory processes in cutaneous tissues: mecha- has been observed with its use. nisms and speculations. J Clin Invest. 1990;86:1783-1789. Infliximab has a half-life of approximately 10 days 3. Kriegler M, Perez C, DeFay K, Albert I, Lu SD. 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symposium will be held on the clinical management of epidermolysis bullosa (EB) in chil- A dren and adults on November 7-8, 2002, at The Institute of Child Health, 30 Guilford St, London WC1N 1EH, England. All individuals and multidisci- plinary teams who care for patients with EB are invited. The meeting is sponsored by DEBRA UK. Those inter- ested in participating should contact DEBRA UK, DEBRA House, 13 Wellington Business Park, Dukes Ride, Crowthorne, Berks RG14 6LS, England; phone: 0044-7779-221909; fax 0044-1344-762777 (e-mail: [email protected]).

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