Psoriasis paradox—infliximab-induced psoriasis in a patient with Crohn’s disease: a case report and mini-review

Abstract

Biologic drugs are therapeutic modalities designed to inhibit specific cytokine signaling pathways. The introduction of these drugs in the management of autoimmune diseases has dramatically changed the treatment paradigm of chronic systemic immune-mediated inflammatory disorders. However, despite their overall acceptable safety profiles, paradoxical reactions have been reported in some real-life cases including case studies and clinical trials. In this study, we report a patient with Crohn’s disease who developed infliximab-induced psoriasis vulgaris after starting infliximab treatment. In this case, infliximab was discontinued, and low-dose steroids and subcutaneous methotrexate were introduced to control both his psoriasis and bowel condition with satisfying responses.

Introduction

Agents targeting the tumor necrosis factor (TNF) family have been approved for the treatment of several systemic autoimmune diseases including rheumatoid arthritis, seronegative spondyloarthritis, and inflammatory bowel syndromes. The introduction of these drugs in the management of autoimmune diseases dramatically changed the treatment paradigm for chronic systemic immune-mediated inflammatory disorders. Despite an overall acceptable safety profile, paradoxical reactions have been reported in some real-life case scenarios. In patients with inflammatory bowel disease (IBD), the use of anti-TNF therapy resulted in successful disease control, especially in steroid-dependent patients or those with refractory disease. Psoriasis and IBD represent a group of chronic, inflammatory, immune-mediated disorders that share pathologic and epidemiologic features. Both disease categories display an overlapping network of innate and adaptive immune responses along with shared genetic susceptibility loci and DNA polymorphisms that lead to observable clinical and therapeutic overlap.^1–3 The co-existence of psoriasis and IBD can extend further from concomitantly to paradoxically as a treatment-related adverse event. ⁴ The treatment armamentarium for either disease incorporates the use of anti-TNF disease-modifying drugs as first-line interventions. However, despite their documented therapeutic efficacy in both diseases, treatment with anti-TNF agents in patients with IBD can induce or worsen psoriatic skin lesions, a condition described as paradoxical psoriasis. The prevalence of TNF inhibitor-induced psoriasis in patients with IBD is estimated to range 1.6% to 2.7%, making it a rare condition in clinical practice. ^{1 , 5 , 6}

Case report

A 21-year-old White man and current smoker presented with joint pain in his lower extremities and psoriatic skin rash on his palms and soles to the Rheumatology and Clinical Immunology Clinic at the Integrated Clinical Research Unit for Intestinal Disorders (ICRID), Department of Tropical Medicine and Hepatogastroenterology, Kasr Alainy School of Medicine, Cairo University. Clinical examination by a rheumatologist revealed asymmetrical arthritis of the knees and ankles. The reporting of this study conforms to the CARE guidelines. ⁷ All patients treated at the ICRID research unit are informed about the possibility of the use of their data in research publications with the preservation of confidentiality and privacy, and written informed consent was obtained. All patient details were de-identified. Upon the receipt of patient consent, the requirement for ethics committee approval is waived at our institution.

Review of the patient’s history

The patient reported being diagnosed with Crohn’s disease 1 year before presentation following complaints of pain in the right iliac region associated with alternating diarrhea and constipation together with anorexia and weight loss. Investigations at that time revealed normal laboratory findings excluding mild anemia hemoglobin (10 g/dL), an erythrocyte sedimentation rate of 56 mm/hour, and a C-reactive protein level of 29 mg/L. His stool was positive for occult blood, and his fecal calprotectin level was 732 µg/mg (normal, 10–50 µg/mg). Levels exceeding 200 µg/mg have a higher positive predictive value for gut pathology, whereas values of 500 to 600 µg/mg strongly support an inflammatory organic pathology in the gastrointestinal tract according to the laboratory reference standards. Colonoscopy revealed that the entire cecum was edematous with erosions and an ulcerated mucosa, whereas the rest of the colon was normal (Figure 1). Biopsies were taken for histopathological examination, which revealed active colitis with neutrophilic infiltration, cryptitis, and crypt abscess. A diagnosis of Crohn’s disease was established according to the collected clinical, laboratory, and colonoscopy evidence. The patient hence started conventional therapy with oral corticosteroids 40 mg/day and azathioprine 200 mg/day, which produced observable improvement of his bowel symptoms. After stabilization of his acute condition, the glucocorticoid dose was reduced to 20 mg/day over 8 weeks while maintaining the same dose of azathioprine, which resulted in symptom recurrence. The patient was classified as steroid-dependent. Biologic therapy was then considered. After obtaining patient consent, the anti-TNF drug infliximab was administered at 5 mg/kg body weight in weeks 0, 2, and 6 with a maintenance infusion every 8 weeks thereafter. The patient reported significant improvement including the cessation of diarrhea after the initiation of infliximab therapy with normalization of inflammatory biomarker levels and a decrease in fecal calprotectin levels to less than 200 µg/mg. The patient decided to discontinue azathioprine 8 weeks after starting infliximab therapy.

Figure 1.

Colonoscopic examination of the patient revealing an eroded cecal mucosa. A biopsy was taken.

After the fifth Infliximab dose, the patient gradually developed erythematous and scaly plaques over his extremities, particularly on the palms and soles. The rash started as small vesicles with desquamation, leaving scales on the palms and soles, for which he sought the advice of a dermatologist. The dermatologist prescribed topical steroid ointments, which provided partial improvement. After 1 week, the scaly lesions became more extensive on the hands and feet despite maintenance infliximab therapy (Figure 2). Skin biopsy revealed typical psoriasis vulgaris.

Figure 2.

Palmoplantar psoriatic lesions with well-demarcated erythematous plaques covered with silvery scales.

At this time, the patient additionally presented with arthralgia in his lower extremities, after which he was referred to a rheumatologist for further assessment. After careful review of the clinical case scenario and the treatment history relative to the onset of the latest clinical presentations, including the improvement of gastrointestinal symptoms and appearance of psoriatic skin lesions, paradoxical psoriasis was considered. Infliximab treatment was then discontinued, and the patient was started on oral prednisolone therapy (40 mg) to prevent the relapse of gastrointestinal inflammation together with subcutaneous methotrexate injection (12.5 mg/week with gradual escalation to 15 mg/week). On follow-up, there were no further clinical signs of gastrointestinal inflammation, and the skin lesions improved significantly with complete resolution within 8 weeks with no further joint complaints. Given the patient’s history of steroid-dependent Crohn’s disease while considering the need to safely withdraw oral corticosteroids, the anti-interleukin-12/23 (IL12/23) agent ustekinumab was considered in case of recurrence of either condition with future steroid withdrawal, but the patient was lost to follow-up after improvement of his skin and gastrointestinal symptoms.

Discussion

Psoriasis is a chronic skin disorder affecting almost 2% of the population. Although biological therapy is a potential therapeutic modality for resistant cases, psoriasis can occur as a paradoxical side effect. ^{8 , 9} Previous studies reported the prevalence of paradoxical psoriasis to be as high as 6.7% in patients with IBD treated with TNF inhibitors, versus 3.1% in their counterparts not receiving biologics. ¹⁰ In a study by Tillack et al., anti-TNFα therapy induced psoriasiform skin lesions in 4.8% of 434 patients with IBD. ¹¹ Conversely, Pugliese and colleagues reported that among 839 patients with IBD, the incidence of paradoxical psoriasis with anti-TNF therapy was 5 per 100 person-years. ¹² Nearly all cases of paradoxical psoriasis were reported as new-onset adverse events after biological treatment, with fewer than 1% of cases occurring as an exacerbation of pre-existing psoriasis. ¹⁰ Patients with IBD who develop anti-TNF therapy-induced psoriatic lesions usually disclose an insignificant personal or family history of psoriasis. Palmoplantar pustulosis was the most common representation of anti-TNF therapy-induced psoriatic lesions developing within 12 months from treatment initiation, ¹³ with up to 40% of patients discontinuing anti-TNF therapy in some studies.^14,15 Smoking and female sex have been associated with a higher risk of TNF inhibitor-induced psoriasis in patients with IBD. ¹⁶ Data regarding the frequency of occurrence of paradoxical psoriasiform eruptions associated with specific anti-TNF drugs revealed that infliximab carried the highest risk (52.6%–62.5%); followed by etanercept (12%–29%), adalimumab (14.4%–34%), certolizumab pegol (1%), and golimumab (0.5%).^17–21 To conclude, evidence supports that TNF inhibitor-induced psoriasis paradox is a class effect rather than a drug effect with the possible risk of recurrence following the reintroduction of either the same drug or another anti-TNF agent. Suggested pathogenetic mechanisms involve the uncontrolled production and upregulation of interferon-α (IFN-α) following TNF inhibition. In a study by Seneschal et al., skin biopsy from 11 patients with paradoxical psoriasiform lesions following TNF-α antagonist therapy revealed increased type 1 IFN and chemokine receptor expression. ²² Another simple explanation for this phenomenon is the simultaneous concurrence of both diseases, as the incidence of psoriasis in patients with IBD ranges from 6% to 11%, compared with 2% to 3% in the general population. However, the observation that most patients reported no history of psoriasis prior to anti-TNF therapy and the complete resolution of the lesions following treatment discontinuation does not strongly support the latter hypothesis. ²³

The treatment of TNF inhibitor-induced psoriasis is challenging, and no clear consensus for specific management exists. In one proposed algorithm, patients with mild psoriasis whose underlying disease is well controlled are recommended to receive a “treat through” approach with traditional therapies for psoriasis. Conversely, for patients with mild skin eruption and uncontrolled underlying disease or patients with moderate-to-severe induced psoriasis with good control of the underlying disease, temporary withdrawal of anti-TNF therapy or switching to other anti-TNF agents could be considered. However, it is important to acknowledge that more than 50% of patients can experience recurrent skin lesions after the reintroduction of either the same drug or a different anti-TNF agent. Thus, for refractory cases of induced psoriasis and for patients with moderate-to-severe skin eruption whose underlying disease is not well controlled, switching the drug class might increase the likelihood of resolving paradoxical psoriasis. ¹⁵ In our case, we stopped the infliximab infusion and introduced low-dose steroids and subcutaneous methotrexate to control both psoriasis and his bowel condition, highlighting the potential use of anti-IL-12/23 therapy as a second-line biologic to be introduced with patient approval.