Background A significant proportion of patients with rheumatoid arthritis continue to have active disease and accrue joint damage despite the use of disease modifying anti-rheumatic drugs (DMARDs) and biologicals including anti-TNF agents and B-cell depletion therapy with rituximab. We have evaluated whether this group of patients respond to treatment with tocilizumab as data on sequential use of tocilizumab after rituximab is deficient.

Objectives To determine the safety and efficacy of tocilizumab in the treatment of active rheumatoid arthritis that is refractory to treatment with both anti-TNF agents and rituximab used in sequence.

Methods Nineteen patients with seropositive (rheumatoid factor and/or anti-cyclic citrullinated peptide antibody) and 6 with seronegative rheumatoid arthritis (RA) (based on American College of Rheumatology diagnostic criteria) were included. The mean age of patients was 54 years and the mean disease duration was 9 years. All had an active disease with a mean DAS28-ESR score (disease activity score-erythrocyte sedimentation rate, DAS28) of 6.1, which was refractory to at least two conventional DMARDs; two anti-TNF agents and rituximab used sequentially. All patients received tocilizumab, (3-48 months after rituximab), intravenously (8mg/kg every 4 weeks). Clinical, laboratory and functional parameters were monitored every 3 months for the duration of follow up of 12 months. Statistical analysis was performed using paired ‘t’ test.

Results At 12 months, 23 patients (92%) had sustained response (DAS28 improved by>1.2) and 10 (40%) were good responders (European League Against Rheumatism response criteria) with DAS28 ≤3.2. None of the patients required an increase in the dose of background DMARDs. Two patients had discontinued treatment due to adverse events (recurrent mouth ulcers and diverticulitis).

At 3 and 12 months, the mean±SD of: DAS28 reduced from 6.1±1.3 to 3.7±1.4 (p= 0.001) and 2.5±0.8 (p <0.0001); tender joint count decreased from 13.8±10.1 to 5.6±7.6 (p= 0.011) and 1.4±2.3 (p= 0.003); and swollen joint count decreased from 5.7±3.7 to 3.2±2.7 (p= 0.2) and 0.8±0.8 (p=0.009), respectively. A significant improvement in patient reported outcomes visual analogue -global (p=0.02) and -pain (p=0.02) scores was noted only by 9 months. An improvement in functional activity was noted in SF-36 (p=0.01), but not FACIT-52 or HAQ scores at 12 months. Also, at 3 and 12 months, the mean±SD of: ESR decreased from 41±33 to 8±11 (p=0.0002) and 8±9 (p=0.001); and C-reactive protein (CRP) from 23±23 to 2±3 (p=0.001), 2±8 (p=0.001), respectively. There was no significant increase in the level of cholesterol or alanine aminotransferase. The neutrophil and platelet count reduced significantly, but remained within the normal range and did not result in adverse events.

Conclusions Sequential use of tocilizumab appears to be well tolerated, safe and effective for anti-TNF- and rituximab-refractory RA. Whereas very rapid control of CRP was achieved within one month, clinical outcome measures continued to improve beyond 3 months. Monitoring of cholesterol, full blood count and liver function tests is warranted.

Disclosure of Interest None Declared