Muhammad Asim Khan

Osteoporosis in Ankylosing Spondylitis

Osteoporosis (OP) is a frequent complication of ankylosing spondylitis (AS), even in early stages of the disease, and is associated with elevated levels of biochemical markers of bone turnover, proinflammatory cytokines, and acute-phase reactants. This suggests that systemic inflammatory mediators, such as interleukin-6 and tumor necrosis factor-α, may be involved. Various factors that conceivably work in conjunction with one another also cause bone loss in AS (eg, genetic polymorphisms of vitamin D, low levels of osteoprotegerin and sex steroid hormones, and impaired calcium and vitamin D absorption). Dual x-ray absorptiometry for assessing bone mineral density (BMD) has limitations in patients with AS because of unreliability of spinal measurements, particularly in advanced disease with new bone formation. Femoral neck BMD is reduced and correlates with increased risk of vertebral fractures. Hence, measurement of BMD at the femoral neck may provide the most accurate means of detecting osteopenia and OP and could assess fracture risk in AS patients. No guidelines are available for detection and treatment of OP in AS, and most patients are young men, who are less likely to be screened. The only evidence-based recommendation is that optimal control of disease activity in AS prevents bone loss. A recent study showed a beneficial effect of infliximab therapy on bone turnover markers and BMD in AS. Also, bisphosphonates may be useful in managing OP in AS.

HLA-B27 and its pathogenic role.

DISCOVERY OF HLA-B27 It was Erik Thorsby from Norway who first described HLA-B27, originally named TH-FJH. It was detected by using an antibody that was produced by “planned immunization,” a method that was being used by several investigators. He immunized a colleague, FJH, with a skin transplant and cells from a healthy donor who was HLA identical with the recipient because Eric assumed that the donor might possess a hitherto undetected HLA antigen. The recipient produced an antibody that detected a “new” antigen, which he named TH-FJH, and this antigen was later given the name HLA-B27. Erik told me that later when he tested his own family, he noticed that one family member who carried this new antigen had AS, whereas another had questionable AS (personal communication). However, since most of his family members who carried the new antigen were completely healthy, he discarded this finding as being caused by chance. He has ever since regretted that he did not pursue this possible association by testing some other patients who suffered from AS. Had he done so he would have been the very first to detect an association between an HLA antigen and a disease!

Remarkable Polymorphism of HLA-B27: An Ongoing Saga

Histocompatibility antigen HLA-B27 is a normal gene that is distributed worldwide with variable prevalence and shows a remarkable association with ankylosing spondylitis and related spondyloarthropathies. The precise biological explanation for this remarkable association remains elusive. HLA-B27 represents a family of closely related proteins encoded by an ever-increasing number of alleles; there are 75 alleles of HLA-B27 known thus far, based on nucleotide sequence differences, but at the translated protein level, there are 62 known subtypes of HLA-B27. Not all subtypes are disease associated. Moreover, existence of a possible hierarchical ranking among some of the subtypes for their disease association has been observed.

Looking into the new ASAS classification criteria for axial spondyloarthritis through the other side of the glass.

The new concept of axial spondylitis (axSpA) and the Assessment of Spondyloarthritis International Society (ASAS) classification criteria for axSpA have induced new clinical research that has broadened our understanding of spondyloarthritis (SpA) and has had indeed a positive impact on earlier diagnosis and treatment of patients with axSpA who have not yet developed radiographic sacroiliitis. The primary goal of any valid classification criteria for any disease is to provide a homogeneous study population with a common etiopathogenesis, similar prognosis, and similar response to identical treatment. Without such a homogeneous study population, robust clinical and basic science research in any subtype of SpA is not possible. All criteria are dynamic concepts that need updating as our knowledge advances and our review of the ASAS classification criteria of axSpA indicates that complex multi-selection design and unclear (not mutually exclusive) definitions of the imaging and clinical arms of the criteria results in patient heterogeneity across study populations. Therefore, there is a need to improve the validity of the ASAS criteria for axSpA. It is our opinion that in the meantime, the clinically well-established entity of AS, as defined by the modified New York (mNY) criteria, should be preserved for the most accurate comparison of the new research studies with those conducted over the last three decades, and that the use of the ASAS criteria should be restricted to patients with nr-axSpA, who are not recognized by the mNY criteria.

A Systematic Review and Meta-analysis of Efficacy and Safety of Novel Interleukin Inhibitors in the Management of Psoriatic Arthritis

Objective The aim of this study was to systemically review the efficacy and safety of inhibitors of interleukin 6 (IL-6): clazakizumab, IL-12/23: ustekinumab, and IL-17A: secukinumab, brodalumab, and ixekizumab in psoriatic arthritis (PsA). Methods The literature search was conducted using MEDLINE, EMBASE, Cochrane Library, Scopus, and Web of Science. We included randomized controlled trials that assessed the efficacy of IL inhibitors and reported American College of Rheumatology 20 response at 24 weeks. Meta-analysis was done using random-effects model utilizing the DerSimonian and Laird method. Quality assessment was done using RobotReviewer Cochrane Risk-of-Bias Assessment Tool. Heterogeneity was assessed with Q statistic and quantified with I2. Publication bias was assessed with a funnel plot. Results Eight studies including 2722 subjects demonstrate the efficacy of IL inhibitors clazakizumab, secukinumab, ixekizumab, brodalumab, and ustekinumab in the treatment of PsA. The American College of Rheumatology 20/50/70 risk ratios were 2.02 (95% confidence interval [CI], 1.65–2.47; P = 0.000), 2.95 (95% CI, 2.32–3.73; P = 0.00), and 5.14 (95% CI, 3.28–8.06; P = 0.00), respectively, in favor of treatment versus placebo. There was no evidence of significant heterogeneity between trials. Subgroup analysis showed efficacy in patients who were tumor necrosis factor naive, as well as tumor necrosis factor nonresponders or inadequate responders. The number of adverse events was higher in the treatment groups versus placebo, the majority were mild and did not require treatment adjustment (risk ratio, 1.17; 95% CI, 1.06–1.28; P = 0.001). There was no significant difference in drug withdrawals. Conclusions Our meta-analysis shows that the inhibitors of IL-6 (clazakizumab), IL-12/23 (ustekinumab), and IL-17A (secukinumab, brodalumab, ixekizumab) are efficacious and generally well tolerated when used to treat patients with PsA.

Treatment of Ankylosing Spondylitis: A Critical Appraisal of Nonsteroidal Anti-Inflammatory Drugs and Corticosteroids

Abstract:Treatment of ankylosing spondylitis and related disorders has been revolutionized by the advent of biological therapy, especially tumor necrosis factor-&agr; inhibitors. Nonsteroidal anti-inflammatory drugs, however, remain the first line of treatment. Evidence has accumulated that nonsteroidal anti-inflammatory drug therapy of ankylosing spondylitis and related disorders is effective in controlling several of the clinical manifestations seen in these disorders, particularly pain, physical function and perhaps progressive spinal fusion. What needs to be proven, however, is the long-term safety profile of these drugs.