Clinical and laboratory markers of disease activity and response to therapy in South Africans with rheumatoid arthritis with disease duration less than two years

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disorder resulting in joint pain, stiffness and joint destruction. This can lead to considerable loss of physical and psycho-social function and even premature death. However, numerous advances in the management of RA have led to remarkable life-changing effects, especially when therapy is initiated early. Joint inflammation occurs following an abnormal immune response to some yet unidentified agent. The inciting agent or process is not well understood but exceptional advances have been made in characterising the molecular and cellular components of the ensuing inflammatory response. This has culminated in the identification of novel therapies and potential biomarkers to enhance patient care. Genetic and environmental factors play an important role with varying clinical manifestations and unpredictable outcomes on an individual basis. Globally, RA accounts for considerable morbidity and of particular concern in the developing world, is the lack of resources that may adversely affect outcome. There is a paucity of research on various aspects of RA in the developing world. This study will review immune-pathogenic aspects of RA, the potential use of clinical features and serological biomarkers and report on aspects of the analysis of a prospective observational study of patients with early RA, prior to starting and 6 months following therapy. A cohort of 171 early RA patients (disease duration less than 2 years) was recruited from the rheumatology clinics of two tertiary academic hospitals, located in Gauteng, South Africa. The objective of the study was to review clinical, demographic, radiological and serological aspects over a two year period. Outcome measures of this study included; i) characterisation of disease burden with respect to both physical and psycho-social aspects; ii) response of disease to therapy in routine care; iii) to characterize auto-antibody, cytokine, cartilage metabolites and genotype profiles associated with disease activity and response to therapy; and iv) clinical and serological measures associated with radiographic damage. Clinical measures included the simplified disease activity index (SDAI) and functional scores (HAQ-DI and SF-36). At baseline and 6 months rheumatoid factor (RF), Anti-citrullinated peptide antibodies (ACPA), circulating cytokines and growth factors were measured. Cartilage metabolites COMP and matrix metalloproteinase (MMP)-3 were measured only at baseline. Genotyping for the shared epitope (SE) HLA-DRB1 allele was performed and classified according to the du Montcel classification. Radiographs of the hands and feet were taken at baseline and at yearly intervals and evaluated for erosive disease and scored according to the Larsen grading system. The cohort recruited was mostly female (140) with a mean age of 47 years. Despite a mean symptom duration of 12 months, patients had severe disease with a mean SDAI of 39.4, with nodulosis and erosive diseases seen in 23% and 51 % respectively. Auto-antibody tests revealed high sensitivity (83%) and specificity (85%) for ACPA with the highest specificity (95%) if both RF and ACPA were positive. Shared epitope positivity was found in 92% of patients and correlated strongly with ACPA. Cytokine levels were globally increased favouring a T helper cell (Th)1, macrophage and pro-angiogenic cytokine profile in certain sub-groups. MMP-3 levels correlated with measures of disease activity but did not perform better than routine laboratory measures such as the C-reactive protein (CRP). Serial measurement of auto-antibodies and cytokine profiles at 6 months revealed significant decreases in tandem with a decrease in disease activity. A more robust decline in cytokine levels was noted in patients who achieved a low disease activity state (SDAI<11) and in patients who received prednisone in addition to methotrexate (MTX). Of the auto-antibodies and biomarkers tested only MMP-3 was predictive (OR 2.8) of an SDAI>11 at 6 months. Only 28% of patients achieved a low disease activity state at 12 months. Predictors of outcome at 12 months included low level of education, unemployment, radiographic damage and a high disease activity. Conclusion: RA in sub-Saharan Africa is strongly associated with SE and ACPA status and a high disease burden at presentation. Despite therapy, only a small percentage of patients achieved an acceptable level of disease activity in routine care underscoring the need for a more aggressive therapeutic approach. Serial measurement of auto-antibodies and cytokines had limited clinical value in routine patient care, but may guide future therapies with the potential to help in stratifying patients. The measurement of serum MMP-3 at baseline may identify a subgroup of patients with a poorer prognosis and hence allow for a more intensive therapeutic approach from the outset.