The Relationship between Smoking, Raynaud's Phenomenon, Digital Ulcers, and Skin Thickness in the Waikato Systemic Sclerosis Cohort.

Objectives: Systemic sclerosis (SSc) is a heterogeneous complex autoimmune connective tissue disease with variable presentation as a consequence of multisystem involvement. One of the key features of SSc is Raynaud's phenomenon along with vascular endothelial dysfunction that leads to digital ulcers (DUs). Raynaud's tends to be triggered by decreasing thermal gradient exposure, while stress and smoking also play a role. DUs arising as a consequence of severe Raynaud's and vasculopathy are a major cause of morbidity and disability in SSc. We set out to determine the relationship between smoking, Raynaud's phenomenon, DUs, and skin thickness in our Waikato Systemic Sclerosis cohort. Methods: The Waikato Systemic Sclerosis (SSc) database was used to extract data. Variables collected included demographics, age of diagnosis, SSc subtypes, age at first non-Raynaud's phenomenon, medications used for treatment of Raynaud's phenomenon or ulcers, and maximal modified Rodnan skin score (mRSS). Raynaud's phenomenon and finger DUs (severity for each over the past week and since diagnosis) and a Scleroderma Health Assessment Questionnaire (SHAQ) visual analog 10 cm scale were collected. The lead rheumatologist completed a physician's assessment of Raynaud's and the disease severity questionnaire. Results: Of the cohort of 143 patients, 100 patients were eligible to complete the questionnaires. Seventy-five patients returned completed questionnaires. Of these, the majority were female (88%), 52 (69.3%) had limited cutaneous systemic sclerosis (lcSSc), 17 (22.7%) had diffuse cutaneous systemic sclerosis (dcSSc), and 6 (8%) had an overlap syndrome. Thirty-six (48%) had a smoking history (in the time frame of collection of serial data). Mean ± standard deviation (SD) pack-years smoked were 17.11 ± 15.29 years. Thirty-five participants had a history of DUs, with a median of 4 DU (range 1-20). Of 17 patients with dcSSc, 12 (70.6%) had ulcers in comparison with 17 of 52 (32.7%) patients with lcSSc. There was a significant relationship between SSc subtype and the number with ulcers (X2 = 10.1, P = 0.007). There was also a significant relationship between physician severity of Raynaud's and presence of ulcers (t = 6.1, P < 0.001), which was not evident between patients' severity of Raynaud's and presence of ulcers (t = 1.9, P = 0.06). On the SHAQ score, smokers had significantly worse Raynaud's phenomenon over the prior week (t = 3.08, P = 0.03) and were more likely to note DUs over the preceding week, although the latter was not statistically significant (t = 1.95, P = 0.055). There was no association between smoking and skin thickness as measured by mRSS (r = 0.23, P = 0.19). Conclusion: Our study demonstrates that smokers have had worse Raynaud's phenomenon over the past week and they were also more likely to note DUs with a trend toward significance but not statistically significant most likely due to our small sample size. Our study also demonstrated that patients with dcSSc had more ulcers in comparison with lcSSc. This study justifies physicians strongly recommending smoking cessation in patients with SSc.

Direct and indirect health-related costs of systemic sclerosis in New Zealand.

AIM: To study the economic impact of systemic sclerosis (SSc) in the patients attending Rheumatology clinics in Waikato Hospital, Hamilton, New Zealand (NZ). There is currently no bottom-up data on this in NZ. METHODS: This is a retrospective cross-sectional questionnaire-based study, including demographics, costs related to SSc, quality of life measures including the short-form survey (SF-36) the scleroderma health assessment questionnaire-visual analog scale (SHAQ-VAS), the NZ index of Deprivation (NZiDep), and work limitations questionnaire (WLQ). Direct health costs include patient-reported costs and costs incurred by the public health system. Indirect costs include calculated loss of work productivity. Comparisons were made between age, gender, disease duration, and disease subtype (diffuse, limited, and overlap syndromes). RESULTS: Participants fulfilled the 2013 ACR/EULAR criteria for SSc. The study was completed by 86 (65.5%) patients, 77 (90%) were females, 19 (22%) had diffuse cutaneous systemic sclerosis (dcSSc), 72 (83%) were NZ European (NZE), seven(8%) were Maori or NZE/Maori. Seventy-six (41.8%) were employed. The average total costs for 6 months were NZ$ 444.50 with the highest costs in the dcSSc sub-group at NZ$ 598.00. The costs incurred by the Hospital for the 2018/2019 fiscal year was NZ$ 3091 per patient. The SF-36 score was lower compared with the general population, mean SHAQ was 0.82. Mean summative WLQ scores were: Time management 21.7, Physical demands 62.5, Interpersonal 23.6, Output demands 23.8. The calculated percentage productivity loss was 46.5%. CONCLUSIONS: This study has shown high health-related costs of SSc in NZ, with reduction in employment, work productivity, and quality of life. The contributors to the costs included physical disability and loss of productivity.

A case of IgG4-related retroperitoneal fibrosis with significant involvement of the abdominal aorta-a clinical and diagnostic challenge.

Immunoglobulin (Ig)G4-related disease (IgG4-RD) with retroperitoneal fibrosis (RPF) is a rare, fibroinflammatory disease involving the soft tissues of the retroperitoneum. A 73-year-old man with IgG4-related RPF affecting the abdominal aorta and iliac arteries was treated with steroids and mycophenolate mofetil. The prevalence of the disease remains unknown because it is often misdiagnosed and can mimic many malignant, infectious, and inflammatory conditions. Autoimmune pancreatitis is a common presenting condition of IgG4-RD. Because As IgG4-RD is responsive to steroids, diagnosing IgG4-related RPF early can prevent the exposure of patients with RPF to unnecessary diagnostic and therapeutic interventions.

Increased malignancies in our Waikato cohort of patients with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) has been associated with an increased risk of malignancy (especially in the skin, lung, breast, and hematological system). AIM: To determine the risk of malignancies in our SSc cohort. METHODS: The NZ National Cancer Registry supplied details of all malignancies recorded in patients attending the Waikato Hospital Systemic Sclerosis Clinics from 2005 to 2018. Prospectively gathered clinical data were used to look for associations between clinical variables and malignancy. RESULTS: Out of the 164 patients in the Waikato SSc cohort, 32 (19.5%) had developed a malignancy. The overall standardized incidence rate was found to be 2.2 (95% CI 1.4-3.4) but was higher for men (4.4, 95% CI 1.4-10.3). The absolute numbers of patients with SSc and malignancies were small and were not adequately powered to investigate the SSc subgroups. The mean age of patients with malignancy was approximately 8 years older than patients without. The most common form of malignancy was skin (14, 43.7%), followed by breast (6, 18.7%), and lymphoma (5, 15.6%). CONCLUSION: This study found an increased risk of malignancy for patients within the Waikato SSc cohort. Risk was greater in male patients and the mean age of patients with malignancies was approximately 8 years older than those without malignancy.

The Emerging Challenge of Pain in Systemic Sclerosis: Similarity to the Pain Experience Reported by Sjogren's Syndrome Patients.

In order to evaluate the importance of pain in systemic sclerosis (SSc), the characteristics of pain reported by patients with SSc were analyzed and compared with the characteristics of pain reported by patients with primary Sjogren's syndrome (pSS). Pain was reported by 56 patients (80%) in a group of 70 patients with SSc and by 25 patients (78%) in a group of 32 patients with pSS. Pain severity was assessed by the Pain Rating Index (PRI) and the Present Pain Intensity (PPI) of the McGill Pain Questionnaire (MPQ) and by values obtained by a visual analog scale (VAS) indicating the intensity of pain felt in the moment of the examination and the intensity of pain felt in the week preceding the moment of the examination. No significant difference was detected in the comparison of mean values of pain indices between patients with SSc and patients with pSS and in the comparison among subgroups of patients with SSc. The data indicate that pain is a frequent and important cause of suffering in SSc as in other chronic diseases. The association of different methods may be especially useful to obtain a careful evaluation of pain in clinical research.

Enthesopathy and involvement of synovio-entheseal complex in systemic sclerosis: an ultrasound pilot study.

OBJECTIVES: SSc is a chronic autoimmune disease characterized by inflammation of the skin and multiple internal organs. Articular involvement is one of the main features of SSc, and typical hallmarks of SpA have been found in SSc patients. The aim of the present study was to estimate the prevalence of entheseal and synovio-entheseal complex (SEC) alterations in a cohort of SSc patients. METHODS: One hundred SSc patients and 25 healthy subjects were included in this cross-sectional study. The enthesis sites of lateral epicondylar common extensor tendons (CET) and the enthesis of the Glasgow Ultrasound Enthesis Scoring System were evaluated. SEC involvement was evaluated only at CET enthesis. RESULTS: In SSc, the Glasgow Ultrasound Enthesis Scoring System score was significantly higher (median 4.0, interquartile range 2.0-7.0) than in controls (median 1.0, interquartile range 0.0-3.0) (P < 0.0001). CET enthesis of SSc patients showed more frequent US B-mode alterations than that of controls (χ2 = 11.47, P = 0.0007 for size; χ2 = 13.79, P = 0.0002 for cortical irregularity, χ2 = 5.24, P = 0.022 for calcification/enthesophytes). Power Doppler US signal at CET enthesis was significantly more frequent in SSc patients than in healthy controls (χ2 = 9.11, P = 0.0025), as was the concomitant SEC involvement (χ2 = 8.52, P = 0.0035). CONCLUSION: These data show that SSc patients frequently present US features of enthesopathy. Moreover, CET enthesopathy was correlated with SEC inflammation, suggesting that entheseal inflammation in SSc may share the same micro-anatomical targets as found in SpA.

Significance of combined anti-CCP antibodies and rheumatoid factor in a New Zealand cohort of patients with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) can present as an overlap syndrome with rheumatoid arthritis (SSc-RA overlap). OBJECTIVE: To evaluate the frequency of rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) in our SSc cohort and their association with clinical features. METHODS: Data were gathered prospectively from the Waikato Hospital Systemic Sclerosis Clinics. Patients with SSc and SOS (systemic sclerosis overlap syndrome) underwent baseline auto-antibody profiling including RF and anti-CCP along with annual clinical review. RESULTS: Our cohort comprised of 132 patients (two had incomplete data); 115 (87.1%) were female. Out of 89 limited cutaneous SSc (lcSSc) patients, arthralgia, synovitis, contractures, tendon crepitus and erosions on imaging were found in three, 10, 31, five and nine patients, respectively. Within the 33 diffuse cutaneous SSc (dcSSc) patients, arthralgia, synovitis, contractures, tendon crepitus and erosion were found in 15, five, 27, five and one patient, respectively. In the 10 SOS patients, arthralgia, synovitis and contractures were found in six, three and two patients; none had tendon crepitus or erosions. RF positivity was found in 15.7%, 9% and 20% of patients with lcSSc, dcSSc and SOS, and anti-CCP positivity was found in 13.5%, 6.1% and 0% in lcSSc, dcSSc and SOS patients. A statistically significant relationship of double antibody positivity with arthralgia (P = 0.03) and erosions (P < 0.001) was found. Anti-CCP positivity association with erosions was significant at P = 0.007. CONCLUSION: Our study confirms that articular manifestations are common in SSc. Statistically significant associations of double antibody positivity with arthralgia and erosions were demonstrated. Significant association between anti-CCP antibody and erosions was also confirmed.

High Prevalence of Antithyroid Antibodies in a New Zealand Cohort of Patients With Systemic Sclerosis.

BACKGROUND: Autoimmune thyroid disease affects 1% of the general population, and autoimmune thyroid antibodies are noted in up to 15%. OBJECTIVE: We hypothesized systemic sclerosis (SSc) is associated with higher prevalence of antithyroglobulin (anti-Tg) and anti-thyroid peroxidase (anti-TPO) antibodies) to justify monitoring of thyroid function for earlier detection and treatment. METHODS: Waikato Hospital SSc clinic patients were prospectively tested for thyroid function tests and antithyroid antibodies (ATAs). RESULTS: Of the 75 patients with SSc and 10 patients with SSc overlap syndrome (SOS) followed up in the SSc clinic, anti-Tg and anti-TPO were prospectively tested in 61 (70.6%) of the 85 patients. The cohort comprised 38 patients with limited cutaneous SSc (lcSSc), 15 with diffuse cutaneous SSc, and 8 with SOS.Anti-Tg and anti-TPO antibodies were found in 34.2% in lcSSc patients and 33.3% in diffuse cutaneous SSc patients, whereas in SOS they were found in 25% (Tg) and in 12.5% (TPO) of patients.At baseline, 10 patients (11.7%) had thyroid dysfunction: 8 (9.4%) with subclinical hypothyroidism and 1 each (1.2%) with subclinical hyperthyroidism and with clinical hyperthyroidism.After 18 months, 1 woman with lcSSc, positive for both ATAs, developed clinical hypothyroidism. CONCLUSIONS: There is a higher prevalence of ATAs in SSc and SOS compared with the general population. Screening these patients for ATAs is a reasonable measure.

Mortality in the Waikato Hospital Systemic Sclerosis Cohort.

OBJECTIVE: To characterize the causes of mortality and standardised mortality ratio in a cohort of patients with systemic sclerosis (SSc). METHODS: A cohort of 132 patients enrolled at the Waikato Systemic Sclerosis Clinic was prospectively followed from 2005 to 2016. Patient demographics, diagnoses and laboratory reports were used to assess risk of mortality and generate standardised mortality ratios (SMR). Survival was analyzed using Kaplan-Meier methods. RESULTS: Of the cohort of 132 patients, 20 (15%) were deceased by the end of the study period. The median age of diagnosis and death was 52 years (range 13-86) and 71 years (range 42-87) respectively. Seventy percent of deaths were SSc related and the leading causes of death were due to pulmonary arterial hypertension (PAH), interstitial lung disease (ILD) and scleroderma renal crisis (SRC). Patients diagnosed after the age of 60 had renal or cardiac manifestations and were associated with a significantly increased risk of mortality. The overall SMR was 2.59 (95% CI 1.67-4.01) and was higher in those with diffuse versus limited SSc (6.46, 95% CI 3.08-13.54 vs. 1.93, 95% CI 1.10-3.41) and males (4.17, 95% CI 1.74-10.02 vs. 2.30, 95% CI 1.39-3.81). CONCLUSION: This study demonstrated an increased risk of mortality in patients with SSc relative to that of the general population. An excess in risk was observed particularly in those with diffuse SSc and in males. Renal and cardiac involvement were found to be significant indicators of mortality and reinforces the necessity of screening for these complications.

Clinical utility of hypo- and hyperpigmentation of skin in diffuse cutaneous systemic sclerosis.

AIM: Cutaneous involvement is an early manifestation of systemic sclerosis (SSc). Localized areas of 'salt and pepper skin' (S&P) may develop. We hypothesize that S&P skin occurs frequently in diffuse cutaneous (dc) SSc which can be used in its early diagnosis and may correlate with joint contractures. METHODS: Sixty-five patients were recruited for this study. The demographic profiles of SSc were ascertained from hospital records. These patients fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria. Patients were examined for skin pigmentary changes, modified Rodnan skin score (mRSS), telengiectasias, calcinosis, arthritis and joint contractures and pruritus. RESULTS: Sixty-five patients (59 female) were recruited with median age of 62.87 years. Forty-four had limited cutaneous SSc, 16 dcSSc, five had scleroderma overlap syndrome. Multivariate stepwise logistic regression indicated that mRSS severity and the presence of contractures were independently (P < 0.05) associated with dcSSc. The strong positive association between S&P and mRSS severity may explain the non-significance of S&P in this analysis. If mRSS severity is not included in the logistic regression analysis, the presence of contractures and S&P (odds ratio = 15.1) show significant (P < 0.01) independent associations with the dcSSc subtype. S&P skin and pruritus were similar in patients with Scl-70 and anti-RNA polymerase antibodies. Anti-centromere antibodies were negatively associated with S&P (χ2 = 7.89, P = 0.005). CONCLUSION: Our study demonstrates strong association of S&P skin with dcSSc (69%), increased risk of pruritus and contractures. Its presence can be used as another clinical tool to diagnose dcSSc in early stages. Observing for S&P skin changes does not require much training.

Development of a Multidimensional Additive Points System for Determining Access to Rheumatology Services.

OBJECTIVE: In many countries, including New Zealand, the demand for rheumatology services exceeds their supply, resulting in some patients experiencing long delays or being denied access. The principal aim of this work was to create a validated, transparent, and fair system for determining access to rheumatology services. METHODS: A panel of 5 rheumatologists, 6 primary care physicians, and 4 nurse specialists ranked a series of 25 clinical scenarios in order of priority to see a rheumatologist. Important determining factors were weighted in an iterative process to generate a multidimensional additive point score to determine access to rheumatology service. RESULTS: The score comprises 6 domains of 2 to 4 items weighted to give a total score out of 100. The effect of the problem on the patient's life and role, the presence of an inflammatory rheumatic disease, appropriateness of current treatment, and the ability of the rheumatologist to influence the current symptoms and future prognosis were felt to be critical factors in determining access to the service. The score showed a strong correlation with the rankings agreed by the clinical panel, and the overall intraclass correlation coefficient for the rheumatologists was 0.698. CONCLUSIONS: Our score has face validity, is easy to perform, and has been assessed by an independent panel of rheumatologists as providing a fair system for determining access to rheumatology services. The system is acceptable to primary care physicians and has been adopted by our local primary care organizations.

Retention on anti-tumour necrosis factor therapy: the Waikato experience.

AIM: To investigate the retention on anti-TNF agents used in a real-world setting, and determine the factors predicting retention on drug. METHOD: Patients starting anti-TNF therapy were recorded prospectively on the departmental database. Medical records of all patients commenced on anti-TNF therapy between 2006 and 2013 at the Rheumatology Department, Waikato Hospital, Hamilton, were retrospectively reviewed to obtain details of their course on biologic therapy. RESULTS: 183 patients were identified. 139 (76.5%) were commenced on adalimumab. The predominant indication was rheumatoid arthritis (52.5%). 60 patients (32.8%) discontinued their initial anti-TNF agent. Of these, 31.7% were due to primary failure, 36.7% due to secondary failure and 25% due to adverse events. At 5 years, retention on agents was: adalimumab (77.2%), etanercept (69.6%) and infliximab (16.7%). Retention on adalimumab was significantly higher than infliximab (p<0.001), but did not differ between adalimumab and etanercept, or etanercept and infliximab. CONCLUSION: In a real-world setting, retention on infliximab was significantly lower than adalimumab.

A cross-sectional study of autoantibody profiles in the Waikato systemic sclerosis cohort, New Zealand.

The autoantibody profiles in New Zealand systemic sclerosis patients have not previously been reported. The aim of this study was to evaluate the autoantibody profiles of patients in the Waikato Hospital Systemic Sclerosis Clinic cohort. The EUROLINE (IgG) Systemic Sclerosis panel test kit (which tests for Scl-70, CENP-A, CENP-B, RP11, RP155, Fib, NOR90, Th/To, PM100, PM75, Ku, PDGFR and Ro-52) was selected for the purpose of this study. All patients attending the Waikato Hospital Systemic Sclerosis clinic were invited to participate. These patients were categorised by systemic sclerosis subtypes [1]. Results were compared with previously published data, including the EUSTAR database. Sixty patients (56 female) were recruited, with a median age of 61 years (range 29-81 years). Forty-one had limited cutaneous systemic sclerosis (lcSSc). Of these lcSSc patients, 31 (75.6%) were positive for CENP-A and CENP-B (anti-centromere) antibodies, 12 (29.3%) for Ro-52 antibodies, 5 (12.2%) for RP11 and RP155, 4 (9.8%) for Scl-70 and 1 (2.4%) each for anti-Fib and Th/To antibodies. Fifteen patients had diffuse cutaneous systemic sclerosis (dcSSc), of which 7 patients (47.6%) were positive for RP11 and RP155, 4 (26.7%) for Scl-70. Three dcSSc patients did not have either of these two major antibodies, but of these 15 dcSSc patients, 4 patients (26.7%) were positive also for Ro-52, 2 (13.3%) for anti-Ku, and 1 (6.7%) each for anti-Fib and NOR90. Four patients had overlap syndrome (OLS), 1 had CENP-A and CENP-B antibodies, 1 had Ro-52 autoantibodies 1 had anti-Ku antibodies. Three patients had no autoantibodies. This is the first study to look at the autoantibody profile of SSc patients in New Zealand. A higher prevalence of antibodies against centromere and RNA polymerase III was demonstrated in our group compared with the EUSTAR database suggesting that antibody prevalence may vary geographically.

Rituximab in diffuse cutaneous systemic sclerosis: should we be using it today?

There is new evidence that B-cell depletion could be an effective intervention in patients with SSc. Observational case-control study data from the European League Against Rheumatism Scleroderma Trials and Research group has suggested that rituximab therapy may reduce progression of skin thickening and lung fibrosis, especially in a subgroup with early dcSSc. These positive data remain preliminary and need to be viewed with caution, recognizing the spontaneous regression of skin thickening that may occur during early disease. In this review, we summarize the clinical evidence for the therapeutic use of rituximab in SSc as well as the basic science evidence suggesting that B cells and autoantibodies are the primary drivers of fibrosis in skin and lung tissue. We have also reviewed the parallels between SSc and the other CTDs where B-cell depletion therapy is efficacious.

A can of red herrings.

Lymphomatoid granulomatosis is a rare disease. Anti-cyclic citrullinated peptide (anti-CCP) antibody is more commonly found in patients with rheumatoid arthritis and less frequently in some of the other rheumatic and non-rheumatic conditions. It is not recognized to be present in lymphoproliferative disease on its own. We report the first case of anti-CCP antibody positivity in lymphomatoid granulomatosis presenting with polyarthritis. This case illustrates the evolving nature of this disease and its characteristics at different stages leading to the challenge of an accurate diagnosis in the setting of a paraneoplastic polyarthritis.