Current concepts in the management of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction that causes significant morbidity and mortality. However, the combined use of methotrexate, a synthetic disease-modifying antirheumatic drug (DMARD), and biologic DMARD has revolutionized treatment of RA. Clinical remission is now realistic targets, achieved by a large proportion of RA patients, and rapid and appropriate induction of remission by intensive treatment with biological DMARD and methotrexate is prerequisite to halt joint damage and functional disabilities. However, biological DMARD is limited to intravenous or subcutaneous uses and orally available small but strong molecules have been developed. Oral administration of tofacitinib targeting the Janus kinase (JAK) is significantly effective than placebo in active patients with methotrexatenaïve, inadequately responsive to methotrexate or tumor necrosis factor (TNF)-inhibitors. The efficacy was rapid and as strong as adalimumab, a TNF-inhibitor. Meanwhile, association of tofacitinib on carcinogenicity and malignancy is under debate and further investigation on post-marketing survey would be warranted. On the other hand, discontinuation of a biological DMARD without disease flare is our next goal and desirable from the standpoint of risk reduction and cost effectiveness, especially for patients with clinical remission. Recent reports indicate that more than half of early RA patients could discontinue TNF-targeted biological DMARD without clinical flare and functional impairment after obtaining clinical remission. Contrarily, for established RA, fewer patients sustained remission after the discontinuation of biological DMARD and "deep remission" at the discontinuation was a key factor to keep the treatment holiday of biological DMARD.

Keywords: Antirheumatic agents; Arthritis, rheumatoid; Biological antirheumatic agents; Janus kinase inhibitor; Remission.

Figure 1.

Composite measures of disease activity: simplified disease activity index (SDAI) and clinical disease activity index (CDAI) and remission criteria using SDAI or CDAI. SJC, swollen joint count; TJC, tender joint count; PGA, patient’s global health assessment (0–10.0 cm visual analogue scale [VAS]); EGA, evaluator’s global health assessment (0–10.0 cm VAS); CRP, C-reactive protein.

Figure 2.

Signaling mechanisms through the Janus kinase (JAK)/STAT pathway and action point of a JAK inhibitor tofacitinib. IL, interleukin; IFN, interferon; G-CSF, granulocyte colony stimulating factor; EPO, erythropoietin; TPO, thrombopoietin; GM-CSF, granulocyte-macrophage colonystimulating factor.

Figure 3.

Development of Janus kinase (JAK) inhibitors. IL, interleukin; IFN, interferon; LIF, leukemia inhibitory factor; OSM, oncostatin M; EPO, erythropoetin; TPO, thrombopoetin; TYK, tyrosine kinase.

Figure 4.

Clinical course of rheumatoid arthritis patients who discontinued adalimumab after obtaining clinical remission by methotrexate and adalimumab. Adapted from Tanaka et al. [34]. DAS28, disease activity score 28; ESR, erythrocyte sedimentation rate; ADA, adalimumab; REM, remission; MTX, methotrexate.

Figure 5.

%Remission and %low disease activity at 1 year after discontinuation of adalimumab in patients with early rheumatoid arthritis (RA) versus established RA. Adapted from Tanaka et al. [34]. DAS28, disease activity score 28; ESR, erythrocyte sedimentation rate.

Figure 6.

Treatment strategy for rheumatoid arthritis to stop joint damage. DAS28, disease activity score 28; SDAI, simplif ied disease activity index; HAQ-DI, Health Assessment Questionnaire disability index; DMARD, disease-modifying anti-rheumatic drug; JAK, Janus kinase.