Anti TNF-µ: A breakthrough in ankylosing spondilytis

This review by Ashu Kansagara & Sachin Kansagara provides the pathogenetic and clinical rationale for the use of anti-TNF alpha agents in the treatment of ankylosing spondilytis

The conventional approach to treatment of patients with spondyloarthritis (SpA), particularly Ankylosing Spondylitis (AS), has serious limitations, adding a sense of urgency to the evaluation of new treatments for these potentially crippling rheumatic disorders. Tumour necrosis factor a (TNFµ) is a cytokine that has been shown to mediate inflammatory and regulatory activities in AS and other immune mediated diseases, including other arthritis and inflammatory bowel disease.

Specifically, TNF-µ directed therapy resulted in significant improvements in disease activity, function, and quality of life in the Ankylosing Spondylitis patients treated with Infliximab. The evidence from various open labels, randomised and controlled long term extension trials suggests sustained clinical benefit with continued use of Infliximab.

Serious side effects were rare and consistent with experience from patient groups receiving Infliximab treatment for inflammatory bowel disease, rheumatoid arthritis and other immune mediated inflammatory diseases (IMIDs) including Ankylosing Spondylitis. Together, these findings herald an age of more effective treatment of patients with AS with biological response modifying agents like anti-TNF-µ monoclonal antibodies.

Ankylosing Spondylitis

Ankylosing Spondylitis (AS), is the primary disease in the group of diseases known as Spondyloarthritis or Spondyloarthropathies. AS is a chronic, systemic, inflammatory disorder involving the axial joints and, frequently, the peripheral joints.

This disease is characterised by stiffness in the lower back and joints at onset, but can progress to severe inflammation in and around the spine as well as in other joints thereby causing extreme pain, stiffness and fatigue. In the most advanced cases (but not in all cases), the inflammation can create scarring in the tissues around the spine that leads to new bone formation, thus forcing the spine to fuse. This fusion may ascend the spine, forming a long, bony column referred to as “bamboo spine.”

Being a systemic disease AS may invariably affect other organs, inflammation of the eyes, gut, lungs, and heart valves are the most common co-morbid disease conditions associated with Ankylosing Spondylitis. Pathogenesis: AS is associated with impairment in the balance of helper T cells subtypes 1 and 2 (Th1 and Th2), demonstrated by reduced T cell production of interleukin 2 (IL2), interferon g (IFNg), and TNF-µ, and increased synthesis of IL10 in the peripheral blood compartment and at the site of the synovial membrane in patients with the disorder.

These findings suggest that impaired Th1 capacity plays a part in the pathogenesis of SpA, possibly through failure of effective bacterial elimination at the initiation of the disease, and that gut mucosal lymphocytes also may actively participate in its development. TNF-µ appears to be abundantly present at the sites of inflammation.

In a study, quantifying T cell cytokine production at the single cell level in patients with AS and healthy controls, a significantly lower percentage of TNF-µ has been found in human leukocyte antigen (HLA)-B27 positive patients with AS and HLA-B27 positive healthy controls as compared with HLA-B27 negative healthy controls . HLA-B27 is strongly associated with AS. It is a protein molecule (known as genetic markers) found on the surfaces of cells.

The HLA markers enable the body’s immune system to distinguish between “self” and “other.” HLA-B27 positive patients with reactive arthritis had lower TNF-µ secretion than HLA-B27 negative patients.

The lower TNF-µ expression at the cellular level may be explained by the occurrence of systemic down regulation, while local concentrations may be high. Ankylosing Spondylitis may be triggered by certain types of bacterial or viral infections that activate an immune response that do not shut off after the infection is healed. The immune system then attacks the body’s own tissue.

Disease progression

Ankylosing Spondylitis causes inflammation of the ligaments and tendons where they connect the vertebrae.

This inflammation causes some damage to the bone, and the body heals this damage by growing new bone.

• This bony growth replaces the elastic soft tissue and can fuse the joints of the vertebrae.
• This fusion causes further stiffness and pain.
• Stiffness and pain usually begins in the pelvis and near the base of the spine and progresses upward through the back to the neck.
• It can also affect the hips and shoulders, the other larger joints of the arms and legs, and the heels.

Treatments for AS need to address the primary aspects of the disorder-that is, inflammatory back pain and stiffness, peripheral arthritis, and enthesopathy. Slowing or regression of disease progression, visualised by radiograph or magnetic resonance imaging (MRI), and improvement in functional ability and quality of life (QoL), are additional desired outcomes. Non-steroidal anti-inflammatory drugs (NSAIDs) often are effective in reducing pain and stiffness but fail to control disease activity or modify the course of the disease.

Second line treatment with sulfasalazine may be most effective in early and active AS with peripheral arthritis 1 2 and may prevent anterior uveitis, but has only modest effects in more severe disease and disease with substantial spinal involvement.

As a result, new treatments are needed to help control this chronic, potentially disabling disorder. Biological agents blocking the major effectors and regulatory cytokine tumour necrosis factor µ (TNF-µ) are among the new treatments currently being investigated in AS. The two major anti-TNF-µ therapies that have demonstrated efficacy in the treatment of AS are the chimeric monoclonal IgG1 antibody infliximab (Remicade; Centocor, Inc, Malvern, PA, USA) and the 75 kDa IgG1 receptor fusion protein etanercept (Enbrel;Immunex Corporation, Seattle, WA, USA). In contrast with conventional treatments, these biological compounds target specific inflammatory and immunoregulatory molecules and events affiliated with AS and spondyloarthritis (SpA).

The use of anti-VBVFB

Several observations strongly implicate TNF-µ in the pathogenesis of AS and suggest the therapeutic potential of anti-TNF-µ agents in this rheumatic disorder.

• Significantly higher TNF-µ serum levels have been found in patients with AS than in patients with non-inflammatory back pain, although the cytokine concentration did not correlate with laboratory or clinical measures of disease activity.
• More recently, high amounts of TNF-µ, messenger RNA and protein were detected in sacroiliac joint biopsy specimens from patients with AS.
• The relationship between AS and inflammatory bowel disease provides further evidence of a role for TNF-µ in AS. Microscopic and macroscopic bowel inflammation resembling early Crohn’s disease has been found in 20-60 per cent of patients with spinal and peripheral arthritis in AS.

AS facts

• Men develop Ankylosing Spondylitis about three times more often than women do. The disorder affects men and women differently.
• Men are more likely to have the inflammation of the spine, pelvis, chest wall, and shoulders.
• Women are more likely to have inflammation of the pelvis, hips, knees, and wrists.
• It most often begins between the ages of 20 and 40, but in some cases it may begin before age 10.
• A tendency to develop Ankylosing Spondylitis runs in families; it is 10 to 20 times more common in people whose parents or siblings have it.
• If one parent has HLA-B27 and Ankylosing Spondylitis, there clearly is some increased risk that the B27 gene and disease will be passed on to a child? However, only about 2 per cent of people with HLA-B27 develop Ankylosing Spondylitis.

Effects of anti-TNF-therapy on spinal manifestations and peripheral arthritis in patents with AS.

Several open label and randomised controlled studies have evaluated the efficacy of the anti-TNF-µ agents infliximab on the axial manifestations and peripheral arthritis of AS (table 1).

The experience with anti-TNF-µ therapy has identified seven types of adverse events that seem to be of particular concern:

• Infections, including sepsis and tuberculosis;
• Malignancies such as lymphoma;
• Haematological disorders such anaemia and panto cytopenia;
• Demyelization disorders and neuropathy;
• Exacerbation of congestive heart failure; production of auto antibodies and autoimmune responses and
• Infusion or injection and hypersensitivity reactions.

Two cases of tuberculosis were reported in randomised placebo controlled investigations of infliximab in SpA, So recommendations about the performance of tuberculin skin testing before infliximab treatment should be carefully considered. Answers to questions about possible predictors of response to anti-TNF-µ therapy, optimal dosing, and timing of the start of treatment in the disease course are also required from future studies. Increased attention should be focused also on the ability of anti-TNF-µ therapy to alter the structural biology of the spine, taking advantage of more sophisticated imaging technology to learn more about the disease’s natural history and its potential modification with pharmacological treatment.

This review provides the pathogenetic and clinical rationale for the use of anti-TNF alpha agents in the treatment of AS, evidence of their Immunomodulatory effects in patients with the disease, and an overview of findings from the previously mentioned international clinical studies.

The writers are with Visveswarapura Institute of Pharmaceutical Sciences, Bangalore