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Published on 23 March 2010

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Tocilizumab used in patients after therapeutic failure: first results

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Tocilizumab (TCZ) represents an interesting new therapeutic class in the treatment of Rheumatoid arthritis (RA) and also offers an alternative mode of action to existing RA treatments

Adeline Quintard

Delphine Grau


Maxime Villiet

PhD

Marie Chemin


Sylvie Hansel-

Esteller
PhD
Pharmacy
Lapeyronie-Arnaud de
Villeneuve Hospital
Montpellier
France

Rheumatoid arthritis (RA) is the most frequently occurring chronic inflammatory type of rheumatism. It is classified in systemic pathology as a consequence of extra articular manifestation, and in autoimmune pathology because of the presence of antibodies. RA is a disease that is affected by genetic, hormonal, environmental, neuropsychological and
immunological factors.

Expert knowledge concerning the pathophysiology of the disease has identified a key substance of the synovial inflammation of RA: tumour necrosis factoralpha (TNF).

TNF’s main role in the pathophysiology of RA (inflammation and osteolysis) is as a pro-inflammatory cytokine, which is based on a dysregulation of cytokinic balance, with an increase of pro-inflammatory cytokines (TNF, interleukin 1, interleukin 6 [IL-6] and interleukin 17) at the expense of anti-inflammatory
cytokines.

IL-6 is responsible for the induction of antibodies in the presence of the rheumatoid factor, activation of Tcells in the synovium, induction of acute phase proteins (increase in C Reactive Protein [CRP], depression of albumin), maturation of megakaryocytes (thrombocytosis) and activation of osteoclasts (bone absorption).[1]

Current treatments target inflammation with disease- modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX) or biological agents. The available biological agents inhibit the action of cytokines (e.g. TNF or interleukin 1) or limit B-cell function or T-cell activation, especially in combination with MTX.

Despite their efficacy, none of these agents leads to a response in all patients, and even among responders the improvement is often limited.[2]

IL-6 is a cytokine that is over-expressed in synovial tissue in patients with RA.[2] New treatments are available, such as tocilizumab (TCZ; RoActemra), following the failure of commercial treatments such as DMARDs and TNF blockers in increasing numbers of patients. TCZ, an investigational agent for the treatment of moderate to severe RA, is a humanised recombinant monoclonal antibody used against soluble or membrane receiving of IL-6, its pro-inflammatory cytokine playing an important pathophysiological role in RA. See figure 1.

Between March 2008 and September 2009, TCZ was given a temporary dispensation for use, but since September 2009, a marketing authorisation has been accorded for TCZ.

TCZ, in combination with MTX, is indicated for the treatment of moderate to severe active RA in adult patients who have either responded inadequately to, or who were intolerant to, previous therapy with one or more disease-modifying DMARDs or TNFα antagonists. In these patients, TCZ can be given as monotherapy in the case of intolerance to MTX or where
continued treatment with MTX is inappropriate.[4] Dosage must not be less than 480mg and not more than 1.2g.

Precautions in treatment must be taken, with dosages being adapted if necessary due to a real haematological toxicity affecting neutrophils and blood platelets, and a hepatic toxicity affecting transaminases.

The objective of this study is to assess the efficiency and tolerance of TCZ among four patients suffering from RA and treated with TCZ.

Design and setting
A prospective monocentric study concerning patients affected by RA treated by TCZ (8mg/kg/infusion) was carried out between November 2008 and June 2009 in the Immune-rheumatology Department of Lapeyronie University Hospital, Montpellier.

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Primary outcome measures
The necessary data are collected by resident pharmacists, using a standardised form to extract results from computerised medical records.

Collection of data
The main assessment criteria were gathered before the first infusion and after each infusion for each medical record. The general criteria were sex, age, weight, dosage received, state of RA (active or not, progressive or not) and previous treatments.

Criteria of efficiency:

1. Disease Activity Score 28 (DAS 28) reflecting activity of RA: pain evaluation and numbers of synovites in 28 articular places, value of erythrocyte sedimentation and general opinion
from patient (see figure 2).
2. Clinical parameters: night awakening, morning stiffness, pain evaluated by the patient, activity disease, numbers of painful anat joints, numbers of flexed anat joints.
3. Inflammatory factors: erythrocyte sedimentation (VS), CRP to evaluate inflammatory syndrome.

Criteria of tolerance:
1. Haematological parameters: neutrophils and blood platelets.
2. Biochemical parameters: creatinine, hepatic enzyme (alanine amino-transferase (ALT), aspartate amino-transferase, gamma-glutamyl transferase (GGT).

Results
The study consisted of four patients: one man and three women, consistent with the average 1:3 sex ratio of RA. The median age was 56 years. All other DMARDs or biological blocker agents were discontinued before the start of the treatment with TCZ: 14 drugs were used on average on each patient.

Results of criteria of efficiency
Median decrease of DAS 28, measured before the first infusion and after the fifth infusion, was Δ1, 81 [α-2.98 ;+1.87α]. An improvement in the disease is noticed with TCZ in relation to the decrease of DAS 28.

Clinically, we saw, on the whole, a reduction in the numbers of night awakening and morning stiffness. Biologically, the medium diminution of erythrocyte sedimentation was Δ17.7. The CRP was Δ18, which led to a significant improvement in inflammation during the evolution of RA. See figure 3.

The worsening of pre-existing haematological disorders in patient 1 (thrombopenia, neutropenia), was observed after the second infusion, which led to a decrease in the dosage to 4mg/kg/infusion. No adverse reactions were reported among the three other patients. No progress in creatinine and hepatic enzymes was noticed, but we observed, in one patient, an increase of GGT below nine times the upper normal limit. See figure 4.

TCZ was found to produce an increase in transaminases concentrations and haematological disorders such as neutropenia and thrombopenia. We recommend that results should be monitored every four to eight weeks for the first six months of treatment, then every 12 weeks thereafter. If transaminases are elevated more than three to five times the upper normal limit, treatment should be suspended. Treatment can be started again once the hepatic enzymes have decreased
below three times the upper limit of normal.

If a thrombopenia and/or a neutropenia appeared, dosage can be reduced by half to 4mg/kg/infusion.[4]

Finally, two patients developed infections, a dental and ORL infection for one, and a urinary infection for the other. Infusions had been reported during infection until eradication.

In patients treated with TCZ 8mg/kg, significant improvements were noted in all individual components of the response including: DAS 28, patient and physician global assessment and pain assessment, and erythrocyte sedimentation and CRP. However, we observed some therapeutic failures predominantly due to haematological disorders.

The safety of TCZ studied in four placebo-controlled studies (OPTION assessing the effectiveness and tolerance of TCZ 4 or 8mg/kg every 4 weeks, TOWARD assessing the efficiency of TCZ among patients in therapeutic failure, RADIATE assessing the efficiency of TCZ associated with MTX among patients in therapeutic failure and AMBITION assessing one MTX-controlled study) had presented adverse drugs reactions.

In all studies, patients treated with TCZ 8mg/kg had a significant reduction in DAS 28 from baseline (mean improvement) of 3.1−3.4 compared with control patients (1.3−2.1). In all, 774 patients received TCZ 4mg/ kg in combination with MTX, 1582 patients received TCZ 8mg/kg in combination with MTX or other DMARDs, and 288 patients received TCZ 8mg/kg in monotherapy.[5]

A neutropenia was observed in our study but we could not determine if neutropenia pre-existed or was attributable to molecule TCZ. We noticed that this patient, who was a therapeutic total failure, had a statistically significant response and continued to improve during treatment.

Caution must be taken in treatment due to a real haematological toxicity affecting neutrophils and blood platelets and a hepatic toxicity affecting transaminases. Monitoring must be done every four to eight weeks to safeguard haematological, hepatic and infectious parameters.

The most commonly adverse drug effects reported were infections (respiratory), hepatic transaminases elevations and haematological abnormalities (decrease in neutrophils and platelets).[4]

Conclusion
The inhibition of receptor IL-6 by TCZ seems to be an effective treatment in RA. It shows a decrease in inflammatory factors and a significant and fast improvement in disease activity (with DAS 28), which result in satisfactory outcomes in patients. However, it is advisable to introduce haematological, hepatic and infectious controls before each infusion and to adapt dosage if necessary. It should be noted that increases in transaminases and levels of cholesterol have been observed among patients treated with TCZ. This study was conducted on four patients, so vigilance in the interpretation of the efficiency and tolerance results must be maintained.

TCZ represents an interesting new therapeutic class in the treatment of RA, but the sustained vigilance of patients is necessary. TCZ offers an alternative mode of action to existing RA treatments.[6]

References
1. Perdriger A. Utilisation des biothérapies en rhumatologie Octobre 2008 université 1 de Rennes.
2. Smolen J, et al. Lancet 371;2008:987−97.
3. Kishimoto T. Arthritis Research & Therapy 8 (Suppl.2);2006:S2.
4. Emery P, et al. The EULAR Journal Ann Rheum Dis doi:10.1136/ard.2008.092932.
5. RoActemra (tocilizumab) Summary of Product Characteristics Roche registration limited. European Medicines Agency, January 2009:2-4.
6. Villoutreix C, et al. Le traitement médical de la polyarthrite rhumatoide en 2005 : des avancées spéctaculaires, Maîtris Orthopédique, October 2005, 147



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