• Infliximab;
  • Magnetic Resonance Imaging;
  • Psoriasis;
  • Psoriatic arthritis;
  • Remicade;
  • Tumor Necrosis Factor α


  1. Top of page
  2. Abstract
  7. Acknowledgements


To evaluate infliximab efficacy and safety in disease-modifying antirheumatic drug–unresponsive psoriatic arthritis (PsA).


In a 54-week, open-label, compassionate-use study, 10 patients received intravenous infliximab (5 mg/kg; weeks 0, 2, 6; individualized dosing after week 10). Patients continued their current therapy (stable dose) until week 10. Assessments were performed at weeks 2, 6, 10, and 54. Magnetic resonance imaging (MRI) objectively measured joint inflammation at weeks 0 and 10.


Patients achieved a 20% improvement according to the American College of Rheumatology (ACR) criteria (ACR20) in all patients by week 2; 8 patients improved 70% (ACR70) at week 10; 6 patients maintained ACR70 after week 54. Week 10 MRI revealed an 82.5% mean reduction in inflammation from baseline, and psoriasis area and severity index scores were reduced by 71.3% ± 16.7%. There were no significant adverse events, severe infections, or infusion reactions.


Infliximab was effective, safe, and well tolerated in PsA. Arthritis and psoriasis improved in all patients during the 54-week evaluation. Further investigation of the use of infliximab for PsA and psoriasis is warranted.


  1. Top of page
  2. Abstract
  7. Acknowledgements

Psoriatic arthritis (PsA) is a spondylarthropathy that occurs in approximately 6–20% of patients with psoriasis (1). There is evidence that tumor necrosis factor α (TNFα) is linked to the pathogenesis of PsA and psoriasis. This proinflammatory cytokine upregulates adhesion molecules and triggers an inflammatory cytokine cascade (2–4), resulting in inflammation and arthritis. Evidence of the involvement of TNFα in the pathophysiology of PsA is based on several findings. First, circulating T lymphocytes and macrophages isolated from PsA patients produce increased TNFα compared with healthy controls (5). The levels of TNFα are elevated in patient synovium, (6, 7) as well as in the skin lesions of PsA patients, (8–10) and TNFα levels correlate with disease activity in psoriasis (11–14). Second, TNF receptors are elevated in synovial fluid and their level of expression correlates with clinical disease severity (15). Finally, a mutation in the promoter region of TNFα is associated with juvenile-onset PsA (16).

The current therapeutic approaches for PsA, similar to those for rheumatoid arthritis (RA), include nonsteroidal antiinflammatory drugs and disease-modifying antirheumatic drugs (DMARDs) such as methotrexate (17), sulfasalazine (18), and cyclosporin A (19). Although the exact mechanism of action of these agents is unknown, they may directly or indirectly downregulate TNFα or other immune mechanisms associated with PsA and RA. Of the current therapeutic options, methotrexate and sulfasalazine are the only 2 agents with well-documented efficacy (20). However, these agents are associated with significant adverse events, and many patients do not respond to these treatments (17, 21).

Because anti−TNFα antibodies (22–24) and fusion proteins (25) have demonstrated efficacy and safety in the treatment of RA, another TNFα–mediated inflammatory arthritis, it was reasoned that they may have efficacy for the treatment of PsA as well. Infliximab is a novel chimeric murine-human monoclonal antibody (cA2, Remicade; Centocor, Malvern, PA) that blocks TNFα, neutralizing both the soluble and membrane-bound forms of the cytokine. In RA patients, it has been demonstrated that, following infliximab therapy, adhesion molecules and inflammatory cytokines known to potentiate inflammation, such as interleukin-6, are downregulated (26). In a recent clinical trial evaluating the efficacy and safety of infliximab and methotrexate combination therapy in RA, 50% of treated patients achieved a 20% or greater improvement according to the American College of Rheumatology (ACR) criteria (ACR20) (27) as early as 2 weeks after treatment, with most patients maintaining an ACR20 response at week 30 (24). Based on clinical trials in RA, infliximab was considered safe and well tolerated. Infliximab has US Food and Drug Administration and European Agency for the Evaluation of Medicinal Products approval for use in RA as well as for the treatment of Crohn's disease (28). However, the potential of infliximab as a treatment for PsA has been previously evaluated in only 9 patients with a rather short observation period of 12 weeks (29).

The objective of the current study was to determine the efficacy and safety of infliximab inhibition of TNFα in PsA patients unresponsive to DMARD therapy. Patient responses to therapy were monitored by magnetic resonance imaging (MRI), an objective measure of inflammation, as well as by standard assessments of arthritis and psoriasis.


  1. Top of page
  2. Abstract
  7. Acknowledgements


Ten patients with a diagnosis of polyarticular disease with persistent clinical and serologic activity despite DMARD therapy were eligible for study inclusion. Seven patients were taking methotrexate, 1 patient was taking sulfasalazine, and 2 patients were not taking DMARDs at the time of inclusion. All patients had psoriatic skin lesions, joint involvement, and x-ray lesions characteristic of PsA. Patients with ≥ 6 tender joints and ≥ 6 swollen joints as well as 1 of 3 baseline criteria (erythrocyte sedimentation rate [ESR] ≥ 25 mm, C-reactive protein [CRP] ≥ 15 mg/L, or morning stiffness ≥ 45 minutes) were included. Patients with a prior history of malignancy, ongoing or recent history of severe infection, pregnancy, or any unstable medical condition were excluded. All patients provided written informed consent. Patients had not previously received infliximab and had no known sensitivity to its components.

Study design.

The study was designed as a single-center, open-label, compassionate-use trial of infliximab. Patients were recruited from the outpatient department of the Department of Medicine III of the University of Erlangen-Nurnberg or after referral from a rheumatologist. Patients were treated within the study center on an outpatient basis.

Infliximab (5 mg/kg) was infused intravenously with normal saline over a 2-hour period. Infliximab treatments were administered at the initial visit (week 0 or baseline) and at weeks 2 and 6, with additional followup evaluation at weeks 10 and 54. Between weeks 10 and 54, patients were treated with infliximab (3 mg/kg) every 8 weeks (with some exceptions; Table 1) on an individual basis determined by their response to infliximab and adverse events reported.

Table 1. DMARD and infliximab treatment history for weeks 10–50*
PatientACR scoreTreatment after week 10
Week 10Week 54DMARDInfliximab
  1. DMARD = Disease-modifying antirheumatic drug; ACR score = American College of Rheumatology criteria; MTX = Methotrexate.

17050MTX5 mg/kg every 8 weeks
27070No DMARD, discontinued MTX after week 10 due to side effects3 mg/kg every 8 weeks
37050MTX3 mg/kg every 8 weeks
47050MTX3 mg/kg every 8 weeks
57070No DMARDDiscontinued month 8; infusion reaction and pregnancy
65070MTXDiscontinued month 5, remission
77070No DMARDDiscontinued month 8, remission
87070MTXDiscontinued month 7, remission
97070MTXDiscontinued week 10, remission
105050No DMARD3 mg/kg every 8 weeks

Patients were allowed to continue stable-dose DMARD (methotrexate [15 to 25 mg/week] or sulfasalazine), steroid (≤ 10 mg/day prednisolone equivalent, stable dose), and nonsteroidal antiinflammatory drug therapy through week 10. After week 10, doses of concurrent medications were adjusted (decreased as appropriate), but no new DMARD or steroid therapy was started. Patients did not receive topical treatment for their psoriasis lesions between weeks 0 and 10.

Patient evaluation.

At weeks 2, 6, 10, and 54, the following assessments were made by the physician: tender joint count (the number of tender joints of 68 possible), swollen joint count (the number of swollen joints of 66 possible), Physician Global Visual Analogue Scale (VAS) of disease severity (0–100 mm VAS, with increasing numbers indicating increasing disease severity). Patients also assessed their pain and disease severity by recording the Patient Global VAS (0–100 mm VAS) of disease severity and the Patient VAS Assessment of Pain (0–100 mm VAS), as well as by completing the Stanford Health Assessment Questionnaire (HAQ, a measure of patient functional disability). Laboratory measurements included CRP and ESR, both of which increase in proportion to disease severity.

Based on the arthritis measures, the stringent response criteria established by the ACR (27) and by Clegg et al (30) were calculated. The ACR criteria for arthritis improvement from baseline are defined as a 20%, 50%, or 70% improvement (ACR20, ACR50, or ACR70, respectively) in the number of swollen and tender joints, with a corresponding improvement in 3 of 5 additional categories (Patient Global VAS, Physician Global VAS, HAQ, ESR, or CRP, and Patient VAS of Pain). Clegg et al (30) defined response to treatment as improvements in 2 of 4 criteria with 1 improvement being joint tenderness or swelling. The 4 criteria are as follows: a 30% improvement in the tender joint count, a 30% improvement in the swollen joint count, an improvement in Physician Global VAS, and an improvement in Patient Global VAS. When applying the Clegg PsA response criteria, no categories may deteriorate.

MRI of gadolinium-diethylenetriaminepentaacetic acid (DTPA) uptake (described in detail below) was determined at baseline and week 10 following infliximab treatment to document changes in joint inflammation.

Psoriasis skin disease was monitored by calculating the psoriasis area and severity index (PASI) (31) for 6 out of 10 patients at weeks 0 and 10. The remaining 4 patients had only very mild skin involvement at baseline and were not evaluated. The PASI scores measure the extent of psoriasis disease as well as the morphology and thickness of psoriasis plaques. The PASI is calculated as follows:

  • equation image

H, t, u, and l represent head, trunk, upper extremities and lower extremities, respectively. Erythema (E), infiltration (I) and desquamation (D) are measured on a scale of 0 to 4 according to the severity of the skin changes. The area (A) is recorded as 0 to 6 according to the percentage of the skin involved. Skin biopsies were obtained from 3 patients at baseline (before treatment) and at week 10. Biopsies were subject to routine histopathologic sectioning, staining, and analysis.

Magnetic resonance imaging.

Because both the Physician and Patient Global VAS are subjective measures of disease severity and because placebo effects occur during DMARD trials for PsA (20), MRI detection of gadolinium-DTPA was employed as an objective measure of inflammation. The amount of gadolinium-DTPA uptake by joints directly correlates with the severity of inflammatory arthritis (32). MRI of gadolinium-DTPA uptake by inflamed joints at baseline (week 0) and week 10 was performed on 8 patients who gave consent to the examination. The patient's inflamed joints were imaged with a 1.5 Tesla magnet (Magneton/Siemens, Erlangen, Germany) as previously described (32). A dynamic flash 2D gradient echo was employed in addition to special superficial coils for optimal resolution. Time-dependent signal intensity changes were measured in 4 defined, enhancing regions of interest after a bolus injection of 0.1 mg/kg gadolinium-DTPA (Magnevist/Schering, Berlin, Germany) following 1 prior unenhanced series. The relative signal intensity (SI) increase (percentage per minute) was calculated at baseline and at week 10 by the following formula:

  • equation image


Vital signs including blood pressure, pulse, and temperature were measured every 30 minutes until 1 hour after the end of the infliximab infusion. Vital sign parameters and laboratory tests (including a blood count with differential, and biochemical tests including electrolytes, urea, creatinine, total protein, and liver enzymes [serum glutamic-pyruvic transaminase, serum glutamic-oxaloacetic transaminase, gamma-glutamyltransferase]) were performed during and after each infusion and again at followup (week 54). Patient-reported adverse events were monitored at each visit and noted by the study evaluator in addition to any adverse events occurring during infliximab infusion.

Statistical analysis.

All data are depicted graphically or in tabular format. Means and standard deviations were calculated for global and peripheral arthritis measures. Two-tailed Mann-Whitney Test (P < 0.05 considered significant) was applied to determine the significance of changes in gadolinium-DTPA uptake.


  1. Top of page
  2. Abstract
  7. Acknowledgements


A total of 10 patients (6 male and 4 female) with a mean age of 34.8 years (range 23–43 years) and a disease duration of 6.6 years (range 1–22 years) were enrolled in the study. All patients exhibited polyarticular disease with stable clinical and serologic activity despite DMARD therapy. All patients presented with elevated CRP and ESR values and experienced morning stiffness for ∼30 to 120 minutes (with the exception of 1 patient who did not experience any morning stiffness). All patients completed infusions at weeks 0, 2, and 6, and were included in the data analysis. Patient treatment was individualized between weeks 10 and 54, based on patient response to infliximab and adverse events.

After week 10, treatment with infliximab was continued or discontinued in 5 patients. Reasons for discontinuation were infusion reaction and detected pregnancy (1 patient), and clinical remission (4 patients). Remission was defined as absence of any active joint inflammation and/or serologic activity (Table 1).


Measures of arthritis severity.

Two weeks following infliximab therapy, improvements were seen in the mean global and peripheral assessments of arthritis severity (Table 2) compared with baseline (week 0). Improvements were noted in Physician Global VAS, Patient Global VAS, HAQ, Patient VAS Assessment of Pain, ESR, and CRP. The number of tender and swollen joints decreased, as did the duration of morning stiffness. Maximum improvements for all global and peripheral assessments were seen at week 10 following infliximab treatment, with improvements maintained in all categories at week 54 compared with baseline.

Table 2. Arthritis assessments*
Response parameterWeek 0Week 2Week 6Week 10Week 54
  • *

    Values are mean (SD). VAS = visual analogue scale; HAQ = Health assessment questionnaire; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate.

Physician Global VAS assessment, mm69.2 (19.0)11.6 (11.4)4.4 (6.9)3.5 (6.9)9.0 (16.5)
Patient Global VAS assessment, mm72.8 (21.0)19.3 (18.4)17.0 (15.9)12.1 (13.5)20.8 (16.0)
HAQ1.05 (0.53)0.5 (0.6)0.28 (0.38)0.28 (0.39)0.39 (0.53)
VAS Pain, mm67.7 (19.6)16.9 (16.2)14.3 (11.6)11.8 (10.1)20.2 (21.4)
CRP, mg/L37.9 (24.4)2.7 (2.5)3.4 (3.7)1.7 (2.1)9.9 (12.4)
ESR, mm35.2 (16.4)10.7 (8.1)8.6 (6.1)10.7 (12.4)15.0 (14.3)
Tender joint count (68)20.6 (15.7)4.5 (5.9)3.6 (6.6)2.1 (4.3)3.6 (7.5)
Swollen joint count (66)14.1 (9.8)2.6 (2.8)2.1 (4.9)1.6 (3.7)2.0 (4.7)
Morning stiffness, minutes58.5 (45.0)16.5 (37.7)15.5 (37.9)12.0 (14.6)18.1 (24.3)

The ACR20, ACR50, and ACR70 responses are summarized in Table 3. By week 2 after infliximab treatment, 10 of 10 patients achieved an ACR20 response, with 8 patients achieving ACR50 and 6 patients achieving ACR70 responses. Additionally, all 10 patients demonstrated ACR50 responses by 6 weeks after the initiation of infliximab therapy. Finally, 8 patients attained ACR70 responses by week 10, with 6 of 10 patients maintaining an ACR70 response at the 54-week followup. Patient responses calculated according to the PsA response criteria established by Clegg et al (21) showed similar patient improvements at week 2 with all patients remaining stable at week 54 after the initiation of infliximab therapy (Table 3). At week 54, 8 of 10 patients still had no tender or swollen joints.

Table 3. American College of Rheumatology (ACR) Criteria and Clegg Criteria responses of 10 patients to infliximab treatment
 Response, no. patients
Week 2Week 6Week 10Week 54
Clegg response10101010
Inflammation measures.

Prior to infliximab treatment, the peripheral joints of 8 patients demonstrated marked inflammation as revealed by MRI detection of gadolinium-DTPA uptake (Figure 1A). The mean gadolinium-DTPA uptake at week 0 was 114%/min (SD ± 73.0% per minute; Figure 2). By the week 10 MRI (Figure 1B) the inflammation was substantially reduced as evidenced by decreased gadolinium-DTPA within the joints (mean, 16.4%/min ± 10.4% per minute; Figure 2). Upon quantitation of the percent reduction in gadolinium-DTPA uptake, it was determined that all patients achieved a reduction in inflammation, with a mean reduction of 82.5% ± 10.3% (P = 0.0071; Table 4).

thumbnail image

Figure 1. Magnetic resonance imaging of gadolinium-diethylenetriaminepentaacetic acid uptake. A,Representative patient foot before and B, 10 weeks after infliximab treatment.

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thumbnail image

Figure 2. Gadolinium-diethylenetriaminepentaacetic acid (DTPA) uptake at baseline (week 0) and week 10 after infliximab treatment. Gadolinium-DTPA uptake based on magnetic resonance imaging, expressed as percentage per minute, was calculated as described in the Methods section.

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Table 4. Reduction of magnetic resonance imaging Gadolinium uptake at week 10
PatientWeek 0*Week 10*% Reduction
  • *

    Values are % per minute.

Psoriasis measures.

As summarized in Table 5, PASI scores improved significantly at week 10 for all 6 evaluated patients, with a mean percent reduction from baseline of 71.3% ± 16.7% (P = 0.0321). Prior to infliximab therapy, 6 PsA patients exhibited characteristic sharply circumscribed erythematous psoriasis plaques covered by silvery scales. By week 10 after infliximab treatment the plaque was almostly completely clear, a response that was typical for all of the 6 patients who had significant skin manifestation at baseline. Upon histopathologic analysis of psoriasis plaques from patient skin, demonstrated a reduction in epidermal hyperplasia and inflammation coinciding with the decrease in plaque size by week 10 of infliximab treatment, as evidenced by the near-normal epidermal structure.

Table 5. Psoriasis Activity and Severity Index (PASI)*
PatientWeek 0Week 10Reduction at Week 10 (%)
  • *

    PASI score described in Methods section.



Infliximab treatment was well tolerated by all patients, with no significant adverse events, severe infections, or infusion reactions. Nine of 10 patients completed the 54-week study, with no patient discontinuations due to adverse events. One patient discontinued infliximab at month 8 because of a mild infusion reaction (facial flushing and myalgia in the extremities) and a detected pregnancy. The infusion reaction was successfully resolved by antihistamine treatment. At term, the patient gave birth to a healthy child. One patient stopped methotrexate therapy because of combined hyperlipidemia. Infliximab treatment was continued in this patient and the abnormal values improved. One patient paused infliximab treatment between months 5 and 12 because of an elective spine operation. There were no reports of dyspnea, urticaria, or headache.


  1. Top of page
  2. Abstract
  7. Acknowledgements

There are few treatment alternatives for patients with progressive PsA who fail to respond to methotrexate. Of the world's population, 1–3% is afflicted with psoriasis (1) and 6–20% of those patients develop PsA (1, 33). In the present study, infliximab, a chimeric antibody that binds to and inactivates TNFα, thereby downregulating inflammatory cytokines and adhesion molecules (26), was administered to PsA patients who had failed to respond to the standard treatment options. Infliximab treatment resulted in an improvement in all global and peripheral assessments of arthritis in all treated patients. Furthermore, applying the stringent response criteria established by the ACR to evaluate RA patient responses to therapy revealed that by week 6 every patient had achieved a 50% improvement in arthritis severity (ACR50)—a response that was sustained by all patients out to week 54 despite lowering the dose or discontinuing infliximab treatment due to remission in some patients. Response criteria defined by Clegg et al (21) also demonstrated that all patients responded to infliximab treatment. Improvements in both arthritis measures were achieved as early as week 2 following the administration of the antibody, and 6 patients continued to meet ACR70 criteria at week 54 after the initiation of infliximab therapy. The MRI analysis provided objective confirmation of the patients' reduced inflammation with a mean reduction in gadolinium-DTPA uptake of 82.5%. Lastly, infliximab appeared to also resolve other manifestations of psoriasis with improvements in PASI indices in addition to a visual reduction in psoriatic plaque size that was confirmed by histopathologic analysis. Within this small cohort we have seen only 1 infusion reaction and no serious adverse events.

The present study was open-label and involved only a small number of patients and no control group. The conclusions that can be drawn from the results are limited. However, our observation that the arthritis measures correlated with MRI data (an objective measure of inflammation) suggests that the responses were due to a true therapeutic effect. The rapid response of clinical parameters, as well as the marked reduction of ESR and CRP, makes a spontaneous reduction of inflammation due to selection criteria unlikely. MRI can be used to visualize the soft tissue abnormalities prior to any further inflammatory damage and is, therefore, a powerful technique for monitoring patients who may be predisposed to arthritis, such as psoriasis patients, as well as for monitoring patient responses to antiinflammatory therapy (34). In the present study MRI was used to document the decrease in inflammation in the joints of infliximab-treated PsA patients. These data, and a previous study using MRI to quantitate the effects of infliximab therapy (32), confirm that MRI, in addition to its current use in diagnosing inflammatory arthritis, is a powerful tool for monitoring antiinflammatory therapy responses.

Data from this study are consistent with those of Van den Bosch et al (29), in which infliximab was used to treat 21 patients with various spondylarthropathies, including 9 patients with PsA. The dose (5 mg/kg infliximab) and treatment regimens were similar between the 2 studies and were modeled after the treatment regimens that have proven efficacious for RA (23). Similar to the current study, Van den Bosch et al documented significant improvements following the first infliximab infusion, with treatment responses maintained through 84 days posttreatment. In addition to the global and peripheral assessments, ESR, CRP, and PASI score measurements presented by Van den Bosch et al, the current study includes ACR and Clegg response data that are more stringent measurements of a drug effect than the individual measures. Additionally, the MRI data objectively quantify the improvement of PsA in response to infliximab. Furthermore, in the present study, patient improvements in psoriasis plaques were observed and examined by histopathologic techniques, confirming the concurrent improvements in skin and joint psoriasis. During a recent double-blind, monocenter study of PsA treatment with etanercept (a TNFα receptor fusion protein), patient improvements according to ACR and Clegg response criteria were also documented (35). In this study 73% of etanercept-treated patients achieved an ACR20 response by week 12 of treatment compared with 13% of patients in the placebo group. The ACR50 and ACR70 responses were 50% and 13%, respectively, for the etanercept-treatment group compared with 3% and 0% in the placebo group. Interpreted together, the present study and the 2 previously published studies highlight the pathophysiologic role of TNFα in PsA and suggest that, similar to RA patients, PsA patients may benefit from infliximab therapy.

In the present study, in the Van den Bosch study (29), and in the etanercept study (35), improvements in PsA were accompanied by improvements in psoriatic plaques. These data suggest that, irrespective of the antigens and cell types driving disease in the skin and joints, both manifestations of psoriasis are dependent to some extent upon TNFα. Therefore, inhibition of TNFα may effectively treat both aspects of the disease.

In conclusion, based on our analysis of this small study, infliximab is effective and safe for the treatment of PsA in patients unresponsive to DMARD therapy. Furthermore, patients also benefited by an improvement in psoriatic plaques. Taken together, the improvement in ACR and Clegg arthritis criteria and the reduction in inflammation detected by MRI, an objective measure of inflammation, suggest that infliximab warrants further investigation for the treatment of psoriatic arthritis.


  1. Top of page
  2. Abstract
  7. Acknowledgements

The authors would like to thank Bettina Raddatz, RN for her excellent assistance during this study.


  1. Top of page
  2. Abstract
  7. Acknowledgements
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