A potential diagnostic serum immunological marker panel to differentiate between primary and secondary knee osteoarthritis.

Inflammation contributes to knee osteoarthritis (KOA) where many immunological mediators participate in its initiation and progression. Most clinicians manage primary (pKOA) and secondary osteoarthritis (sKOA) alike. Whether immunological profiles of pKOA and sKOA differ remains obscure. Hence, we aimed to differentially identify potential serum immunologic diagnostic markers of pKOA and of sKOA. This case control study used 46 KOA patients (pKOA, n = 30; sKOA, n = 16), and 60 age, gender matched controls (normal healthy, n = 30; systemic lupus erythematosus [SLE] disease controls, n = 30) where serum was assayed for cytokines (TNF-α, IL-1ß, IL-6, IL-10) and nitric oxide derivatives (NOx). Sandwich ELISA assessed cytokine levels, while the 'Griess assay' quantified NOx levels. The diagnostic accuracy of optimal marker combinations was evaluated by the CombiROC web tool. Compared with pKOA, sKOA serum displayed significantly elevated levels of pro inflammatory cytokines (TNF-α, IL-1ß, IL-6) with a concurrent decrease in the anti-inflammatory cytokine, IL-10 (P<0.05). This was reiterated by significantly higher Th1:Th2 (TNF-α: IL-10) serum cytokine ratio observed in sKOA compared to that of pKOA. The CombiROC curves identified TNF-α, IL-1ß, IL-6 and NOx as the best performing panel of potential diagnostic markers to discriminate pKOA from control groups (~97% accuracy, 90% Sensitivity [SE] and 98% specificity [SP]), while TNF-α, IL-1ß and IL-6 discriminated sKOA from control groups (~100% accuracy, 100% SE, and 98% SP). The study identified discrete serum immune biomarker panels to differentiate between pKOA (TNF-α, IL-1ß, IL-6 and NOx) and sKOA (TNF-α, IL-1ß and IL-6). These findings may assist in developing distinct therapeutic agents for the two types of KOA.

Is being barefoot, wearing shoes and physical activity associated with knee osteoarthritis pain flares? Data from a usually barefoot Sri Lankan cohort.

AIM: To identify the association between hours of being barefoot/wearing footwear, physical activity (PA) and knee osteoarthritis pain flares (KOAF). METHODS: Persons with a diagnosis of knee osteoarthritis, who reported previous KOAF, were followed up in a 3 months long telephone-based case-crossover study. Exposures to risk factors were assessed every 10 days and whenever the participants experienced a KOAF. Conditional logistic regression examined associations of KOAF with following: hours of being barefoot/using footwear and PA performed (P < .05). RESULTS: There were 260 persons recruited, of whom 183 continued longitudinal follow up. Of them, 120 persons had at least one valid KOAF and control period. Participants were female (90%) with mean (SD) age and body mass index of 59.9 (7.0) years, 28.0 (5.0) kg/m2 respectively. Participants were barefoot for a mean duration of 12.7 hours (SD 4.6) and used footwear for 5.1 (SD 4.7) hours daily; 99% wore heel heights <2.5 cm. Duration of being barefoot, 1 and 2 days before, demonstrated reduced multivariate odds of KOAF (odds ratio [OR] = 0.85; 95% CI 0.80-0.90). Moderate PA performed 1, 2 days prior was associated with a significantly increased risk of KOAF (multivariate OR 4.29; 2.52-7.30 and OR 3.36; 2.01-5.61). Similarly, hours of using footwear 1 and 2 days before flare demonstrated increased odds of KOAF (OR 1.15; 1.07-1.23 and 1.10; 1.03-1.18). CONCLUSIONS: Increased duration of being barefoot 1 to 2 days before is associated with reduced risk of KOAF. Performing moderate PA 1 to 2 days before was associated with an increased risk of KOAF.

Chronic low back pain and its association with lumbar vertebrae and intervertebral disc changes in adults. A case control study.

AIM: This study was done to determine the association between chronic low back pain and vertebral fractures, intervertebral disc space (IDS) narrowing, vertebral osteophytes and spondylolisthesis among adults. METHOD: This case control study was done in Sri Lanka. Cases were patients with low back pain and controls were without low back pain. Postero-anterior and lateral radiographs of lumbar sacral spine of both groups were studied. To detect vertebral fractures in fourth and fifth lumbar vertebrae, anterior and posterior heights of vertebrae were measured using a Vernier caliper and antero-posterior ratio (A/P) was calculated. Having an A/P ratio value of < 0.89 was considered as a vertebral fracture. Presence of disc space narrowing, vertebral osteophytes and spondylolisthesis was assessed by two radiologists working independently. Bivariate and logistic regression analysis was done to find associations. RESULTS: There were 140 cases and 140 controls. Mean (SD) age for cases was 51.6 (17) years. Mean (SD) age for controls was 50 (15) years. Females made up 62% of cases and controls. Fifth lumbar vertebral fracture (odds ratio [OR] = 10.2; P = 0.001), fourth lumbar vertebral fracture (OR = 2.5; P = 0.017) and IDS narrowing (OR = 4.15, P = 0.009) had a significant association with low back pain and vertebral osteophytes and spondylolisthesis did not have a significant association with low back pain. CONCLUSION: Only vertebral fractures and IDS narrowing had a significant association with chronic low back pain.

A Case of Polyarteritis Nodosa Presenting as Rapidly Progressing Intermittent Claudication of Right Leg.

BACKGROUND: Polyarteritis nodosa (PAN) is a medium vessel vasculitis which causes significant morbidity and mortality. Usually, it presents with constitutional symptoms with angiographic evidence of aneurysms or segmental stenosis of arteries of mesenteric or renal vasculature. It is exceedingly uncommon for PAN to present with symptomatic progressive intermittent claudication. CASE PRESENTATION: We describe a 60-year-old male who presented with rapidly progressive intermittent claudication of his right leg. He did not have any significant atherosclerotic risk factors. He had recent onset hypertension and loss of weight. He also had mononeuropathy of right common peroneal nerve and livedo reticularis rash. With negative autoimmune markers and suggestive histology in deep punch skin biopsy and angiographic evidence of segmental stenosis of femoral and renal arteries, we diagnosed PAN. We treated him with aggressive immunosuppressants and vascular bypass surgery of right femoral vessels; he showed a good response. CONCLUSION: Rapidly progressive unilateral intermittent claudication could be a very rare, but noteworthy presentation of PAN. With suggestive histology and exclusion of other comorbidities aggressive immunosuppressants should be instituted. Vascular bypass surgery for critical ischaemia of the limbs is an option that could be considered for limb-threatening disease.

Variants of ACAN are associated with severity of lumbar disc herniation in patients with chronic low back pain.

INTRODUCTION: Disc herniation is a complex spinal disorder associated with disability and high healthcare cost. Lumbar disc herniation is strongly associated with disc degeneration. Candidate genes of the aggrecan metabolic pathway may associate with the severity of lumbar disc herniation. OBJECTIVES: This study evaluated the association of single nucleotide variants (SNVs) of the candidate genes of the aggrecan metabolic pathway with the severity of lumbar disc herniation in patients with chronic mechanical low back pain. In addition, we assessed the in-silico functional analysis of the significant SNVs and association of their haplotypes with the severity of lumbar disc herniation. METHODS: A descriptive cross sectional study was carried out on 106 patients. Severity of disc herniation and disc degeneration were assessed on T2-weighted mid sagittal lumbar MRI scan. Sixty two exonic SNVs of ten candidate genes of aggrecan metabolic pathway (ACAN, IL1A, IL1B, IL6, MMP3, ADAMTS4, ADAMTS5, TIMP1, TIMP2 and TIMP3) were genotyped on a Sequenom MassARRAY iPLEX platform. Multivariable linear regression analysis was carried out using PLINK 1.9 software adjusting for age, gender, body mass index and severity of disc degeneration. Four online bioinformatics tools (Provean, SIFT, PolyPhen and Mutation Taster) were used for in-silico functional analysis. RESULTS: Mean age was 52.42 ± 9.42 years and 69.8% were females. The mean severity of disc herniation was 2.81 ± 1.98. The rs2272023, rs35430524, rs2882676, rs2351491, rs938609, rs3825994, rs1042630, rs698621 and rs3817428 variants and their haplotypes of ACAN were associated with the severity of lumbar disc herniation. However, only the rs35430524, rs938609 and rs3817428 variants of ACAN were detected as pathogenic by in-silico functional analysis. CONCLUSIONS: SNVs of ACAN and their haplotypes are associated with the severity of lumbar disc herniation. Functional genetic studies are necessary to identify the role of these significant SNVs in the pathogenesis of disc herniation.

Leflunomide is equally efficacious and safe compared to low dose rituximab in refractory rheumatoid arthritis given in combination with methotrexate: results from a randomized double blind controlled clinical trial.

BACKGROUND: The standard dose of rituximab used in rheumatoid arthritis (RA) is 1000 mg but recent studies have shown that low dose (500 mg) is also effective. Efficacy of low dose rituximab in rheumatoid arthritis (RA) refractory to first-line non-biologic Disease Modifying Anti Rheumatic Drugs (DMARDs), compared to leflunomide is unknown. In a tertiary care referral setting, we conducted a randomized, double blind controlled clinical trial comparing the efficacy and safety of low-dose rituximab-methotrexate combination with leflunomide-methotrexate combination. METHODS: Patients on methotrexate (10-20 mg/week) with a Disease Activity Score (DAS) > 3.2 were randomly assigned to rituximab (500 mg on days 1 and 15) or leflunomide (10-20 mg/day). The primary end-point was ACR20 at 24 weeks. Sample of 40 had 70% power to detect a 30% difference. ACR50, ACR70, DAS, EULAR good response, CD3 + (T cell), CD19 + (B cell) and CD19 + CD27+ (memory B cell) counts, tetanus and pneumococcal antibody levels were secondary end points. RESULTS: Baseline characteristics were comparable in the two groups. At week 24, ACR20 was 85% vs 84% (p = 0.93), ACR50 was 60% vs. 64% (p = 0.79) and ACR70 was 35% vs 32% (P = 0.84), in rituximab and in leflunomide groups respectively. Serious adverse events were similar. With rituximab there was significant reduction in B cells (p < 0.001), memory B cells (p < 0.001) and pneumococcal antibody levels (P < 0.05) without significant changes in T cells (p = 0.835) and tetanus antibody levels (p = 0.424) at 24 weeks. With leflunomide, significant reduction in memory B cells (p < 0.01) and pneumococcal antibody levels (p < 0.01) occurred without significant changes in B cells (P > 0.05), T cells (P > 0.05) or tetanus antibody levels (P > 0.05). CONCLUSIONS: Leflunomide-methotrexate combination is as efficacious as low-dose rituximab-methotrexate combination at 24 weeks, in RA patient's refractory to initial DMARDs. The high responses seen in both groups have favorable cost implications for patients in developing countries. Changes in immune parameters with leflunomide are novel and need further characterization. TRIAL REGISTRATION: The trial was registered with the Sri Lanka Clinical Trials Registry (SLCTR), a publicly accessible primary registry linked to the registry network of the International Clinical Trials Registry Platform of the WHO (WHO-ICTRP) (registration number: SLCTR/2008/008 dated 16th May 2008).

Associations between disc space narrowing, anterior osteophytes and disability in chronic mechanical low back pain: a cross sectional study.

BACKGROUND: Radiographic features of lumbar disc degeneration (LDD) are common findings in patients with chronic mechanical low back pain; however, its role in disability and intensity of pain is debatable. This study aims to investigate the associations of the x-ray features of LDD and lumbar spondylolisthesis with severity of disability and intensity of pain. METHODS: A cross-sectional study was conducted on 439 patients with chronic mechanical low back pain who attended the rheumatology clinic, National Hospital of Sri Lanka, Colombo, from May 2012 to May 2014. Severity of disability was measured using Modified Oswestry Disability Index and intensity of pain was assessed using numeric rating scale (0-100). X-ray features of LDD (disc space narrowing, anterior osteophytes and overall LDD) and spondylolisthesis were assessed in lateral recumbent lumbar x-rays (L1/L2 to L5/S1) and graded by a consultant radiologist blinded to clinical data. Generalised linear model with linear response was used to assess the associations of x-ray features of LDD with severity of disability and intensity of pain adjusting for age, gender, body mass index and pain radiating into legs. RESULTS: Mean age was 48.99 ± 11.21 and 323 (73.58%) were females. 87 (19.82%) were obese. Mean severity of disability was 30.95 ± 13.67 and mean intensity of pain was 45.50 ± 20.37. 69 (15.72%), 26 (5.92%) and 85 (19.36%) patients had grade 2 disc space narrowing, anterior osteophytes and overall LDD, respectively. 51 (11.62%) patients had lumbar spondylolisthesis. Grade of disc space narrowing and overall LDD were not associated with severity of disability or intensity of pain. The presence of lumbar spondylolisthesis was associated with severity of disability. Female gender and pain radiating into legs were associated with severity of disability and intensity of pain. Advancing age was associated with x-ray features of LDD and lumbar spondylolisthesis. CONCLUSIONS: Lumbar spondylolisthesis is associated with severity of disability in patients with chronic mechanical low back pain. Associations of x-ray features of LDD with severity of disability and intensity of pain are inconclusive. Female gender and pain radiating into legs are significant confounders.

Pregnancy outcomes and contraceptive use in patients with systemic lupus Erythematosus, rheumatoid arthritis and women without a chronic illness: a comparative study.

OBJECTIVES: To compare the pregnancy outcomes and contraceptive practices in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and women with no chronic illness (WNCI) in a tertiary care referral center in Colombo, Sri Lanka. METHODS: Patients with SLE satisfying American College of Rheumatology criteria for diagnosis and history of pregnancies were recruited from university lupus clinic, National Hospital of Sri Lanka (NHSL). Age-matched women with history of pregnancy and RA were recruited from the rheumatology clinic, NHSL and WNCI from a surgical clinic. RESULTS: In 71 patients with SLE, 79 pregnancies occurred in 38 patients. The number of total pregnancies in SLE, RA and WNCI (79, 80 and 85 respectively) were not significantly different (P > 0.05), but most occurred before diagnosis of SLE and RA. Pregnancies occurring after diagnosis were significantly higher in SLE compared to RA (P = 0.013, χ2 = 6.169). Mean age at diagnosis was higher (P < 0.01) in RA (35 years) than in SLE (26 years). Percentage live births after diagnosis was significantly lower (P < 0.01) in SLE (9/20; 45%) compared to RA (6/8; 75%) and WNCI (77/85; 91%). Adverse fetal outcomes (fetal loss, pre-maturity, low birth weight) and assisted deliveries were significantly more (P < 0.001) in SLE than in WNCI. Unplanned pregnancies were significantly higher (P < 0.01) in SLE (80%) compared to RA (25%) and in WNCI (9.4%). Contraceptive usage was lower in patients with SLE (25.6%) and RA (33%) compared to WNCI (56.4%). Disease exacerbations occurred in 20% of SLE patients during pregnancy. CONCLUSIONS: More pregnancies occur in SLE than in RA after diagnosis of illness. Unplanned pregnancies and adverse pregnancy outcomes need to be addressed more in SLE than in RA or in WNCI.

Single Nucleotide Variants of Candidate Genes in Aggrecan Metabolic Pathway Are Associated with Lumbar Disc Degeneration and Modic Changes.

INTRODUCTION: Lumbar disc degeneration (LDD) is genetically determined and severity of LDD is associated with Modic changes. Aggrecan is a major proteoglycan in the intervertebral disc and end plate. Progressive reduction of aggrecan is a main feature of LDD and Modic changes. OBJECTIVES: The study investigated the associations of single nucleotide variants (SNVs) of candidate genes in the aggrecan metabolic pathway with the severity of LDD and Modic changes. In-silico functional analysis of significant SNVs was also assessed. METHODS: A descriptive cross sectional study was carried out on 106 patients with chronic mechanical low back pain. T1, T2 sagittal lumbar MRI scans were used to assess the severity of LDD and Modic changes. 62 SNVs in ten candidate genes (ACAN, IL1A, IL1B, IL6, MMP3, ADAMTS4, ADAMTS5, TIMP1, TIMP2 and TIMP3) were genotyped on Sequenom MassARRAY iPLEX platform. Multiple linear regression analysis was carried out using PLINK 1.9 in accordance with additive genetic model. In-silico functional analysis was carried out using Provean, SIFT, PolyPhen and Mutation Taster. RESULTS: Mean age was 52.42±9.42 years. 74 (69.8%) were females. The rs2856836, rs1304037, rs17561 and rs1800587 variants of the IL1A gene were associated with the severity of LDD and Modic changes. The rs41270041 variant of the ADAMTS4 gene and the rs226794 variant of the ADAMTS5 gene were associated with severity of LDD while the rs34884997 variant of the ADAMTS4 gene, the rs55933916 variant of the ADAMTS5 gene and the rs9862 variant of the TIMP3 gene were associated with severity of Modic changes. The rs17561 variant of the IL1A gene was predicted as pathogenic by the PolyPhen prediction tool. CONCLUSIONS: SNVs of candidate genes in ACAN metabolic pathway are associated with severity of LDD and Modic changes in patients with chronic mechanical low back pain. Predictions of in-silico functional analysis of significant SNVs are inconsistent.

Effect of parity on phalangeal bone mineral density in post-menopausal Sri Lankan women: a community based cross-sectional study.

There is paucity of studies related to parity and bone mineral density in South Asian countries. We recruited 713 healthy, community dwelling post-menopausal women from seven provinces in Sri Lanka for this survey. The number of pregnancies, including miscarriages beyond 20 weeks of gestation, was recorded. Women with diseases and those who have taken drugs that can affect bone mineral density (BMD) were excluded (n = 15). Phalangeal BMD and bone mineral content (BMC) were measured using AccuDEXA in 713 women. Mean (SE) BMD of nulliparous women (n = 32), women with one to two pregnancies (n = 284), three to four pregnancies (n = 290) and more than four pregnancies (n = 107) were 0.437(0.014), 0.454(0.005), 0.455(0.005) and 0.417(0.006) g/cm(2), respectively (P < 0.001). Corresponding mean (SE) BMCs were 1.30(0.063), 1.41(0.021), 1.43(0.022) and 1.32(0.033) g, respectively (P < 0.001). Women with more than four pregnancies were older and lighter when compared with other groups. When results were adjusted for current age and current weight, differences in mean BMD and BMC between groups became non-significant. BMD of nulliparous women remained low in all analyses. We report a significant difference in unadjusted phalangeal BMD in women categorized according to their parity. Women with one to four pregnancies had the highest phalangeal BMD and BMC, while multi-parous (more than four pregnancies) and nulliparous women had lower values. However, in an adjusted analysis, the differences in BMD and BMC were partially explained by the differences of age and body weight between the groups and the unique effect of parity was difficult to determine. Women with lower BMD may have a higher risk of future fractures.

Prevalence and determinants of osteoporosis among men aged 50 years or more in Sri Lanka: a community-based cross-sectional study.

SUMMARY: This study, based on phalangeal bone mineral density (BMD) of 1,174 community dwelling male volunteers aged 50 years or more from seven provinces in Sri Lanka, shows 5.8% prevalence of osteoporosis among them. Advancing age, less physical activity, and low body weight were associated with low BMD. Men with larger families were more likely to have a lower bone mineral density. PURPOSE: The prevalence of osteoporosis among Sri Lankans is not well-known. We wished to estimate the prevalence and determinants of osteoporosis among older men in Sri Lanka. METHODS: One thousand one hundred seventy-four healthy, community dwelling male volunteers, aged 50 years or more from seven out of nine provinces in Sri Lanka underwent phalangeal bone mineral density estimation using an AccuDXA(R) scanner. We calculated T scores using the local reference data, and subjects with T score equal or less than -2.5 was considered to have osteoporosis. RESULTS: Sixty-six men (5.8%) were detected to have osteoporosis. In contrast to men in the highest tertile of bone mineral density, men in the lowest tertile were older (60.0 versus 55.8 years, p < 0.001), lighter (56.3 versus 65.6 kg, p < 0.001), less physically active (16.1% versus 5.5%, p < 0.001) and had larger families consisting of four or more children (36% versus 20.9%, p < 0.001). Smoking, alcohol, or milk consumption showed no association with bone mineral density. CONCLUSIONS: We report 5.8% prevalence of osteoporosis among men older than 50 years in Sri Lanka, and advancing age, less physical activity, and low body weight were associated with low bone mineral density. Men with larger families were more likely to have a lower bone mineral density.