Gianluca Sambataro

Regional Implantation of Autologous Adipose Tissue-Derived Cells Induces a Prompt Healing of Long-Lasting Indolent Digital Ulcers in Patients with Systemic Sclerosis:

Digital ulcers (DUs) are a rather frequent and invalidating complication in systemic sclerosis (SSc), often showing a very slow or null tendency to heal, in spite of the commonly used systemic and local therapeutic procedures. Recently, stem cell therapy has emerged as a new approach to accelerate wound healing. In the present study, we have tentatively treated long-lasting and poorly responsive to traditional therapy SSc-related DUs by implantation of autologous adipose tissue-derived cell (ATDC) fractions. Fifteen patients with SSc having a long-lasting DU in only one fingertip who were unresponsive to intensive systemic and local treatment were enrolled in the study. The grafting procedure consisted of the injection, at the basis of the corresponding finger, of 0.5-1 ml of autologous ATDC fractions, separated by centrifugation of adipose tissue collected through liposuction from subcutaneous abdominal fat. Time to heal after the procedure was the primary end point of the study, while reduction of pain intensity and of analgesic consumption represented a secondary end point. Furthermore, the posttherapy variation of the number of capillaries, observed in the nailfold video capillaroscopy (NVC) exam and of the resistivity in the digit arteries, measured by high-resolution echocolor-Doppler, were also taken into account. A rather fast healing of the DUs was reached in all of the enrolled patients (mean time to healing 4.23 weeks; range 2-7 weeks). A significant reduction of pain intensity was observed after a few weeks (p < 0.001), while the number of capillaries was significantly increased at 3- and 6-month NVC assessment (p < 0.0001 in both cases). Finally, a significant after-treatment reduction of digit artery resistivity was also recorded (p < 0.0001). Even with the limitations related to the small number of patients included and to the open-label design of the study, the observed strongly favorable outcome suggests that local grafting with ATDCs could represent a promising option for the treatment of SSc-related DUs unresponsive to more consolidated therapies.

Nailfold videocapillaroscopy micro-haemorrhage and giant capillary counting as an accurate approach for a steady state definition of disease activity in systemic sclerosis

IntroductionNailfold videocapillaroscopy (NVC) in systemic sclerosis (SSc) is a procedure commonly used for patient classification and subsetting, but not to define disease activity (DA). This study aimed to evaluate whether the number of micro-haemorrhages (MHE), micro-thrombosis (MT), giant capillaries (GC), and normal/dilated capillaries (Cs) in NVC could predict DA in SSc.MethodsEight-finger NVC was performed in 107 patients with SSc, and the total number of MHE/MT, GC, and the mean number of Cs were counted and defined as number of micro-haemorrhages (NEMO), GC and Cs scores, respectively. The European Scleroderma Study Group (ESSG) index constituted the gold standard for DA assessment, and scores ≥3.5 and =3 were considered indicative of high and moderate activity, respectively.ResultsNEMO and GC scores were positively correlated with ESSG index (R = 0.65, P <0.0001, and R = 0.47, P <0.0001, respectively), whilst Cs score showed a negative correlation with that DA index (R = -0.30, P <0.001). The area under the curve (AUC) of receiver operating characteristic plots, obtained by NEMO score sensitivity and specificity values in classifying patients with ESSG index ≥3.5, was significantly higher than the corresponding AUC derived from either GC or Cs scores (P <0.03 and P <0.0006, respectively). A modified score, defined by the presence of a given number of MHE/MT and GC, had a good performance in classifying active patients (ESSG index ≥3, sensitivity 95.1%, specificity 84.8%, accuracy 88.7%).ConclusionsMHE/MT and GC appear to be good indicators of DA in SSc, and enhances the role of NVC as an easy technique to identify active patients.

Present and future of biologic drugs in primary Sjögren’s syndrome

ABSTRACT Introduction: Primary Sjögren’s (pSS) syndrome is a chronic, autoimmune, and systemic disease characterized by xerostomia, xerophthalmia, muscle pain and fatigue. The disease may be complicated by a systemic involvement, such as a pulmonary fibrosis or the development of lymphoma which severely worsens the prognosis. Actually, there are no recommendations for the management of pSS. However, recent advances in the understanding of its pathogenesis have uncovered some pathways that have potential as therapeutic targets. Areas covered: In this review, the authors present the biologic drugs potentially valuable to the treatment of pSS in light of its physiopathology with a ‘bird’s eye’ view of future prospects. The authors took into account relevant studies published from 2004 to 2016. Expert opinion: Biological treatment in pSS is a promising opportunity to potentially control disease activity and prevent its complication. Currently, inhibition of B-cell and IL-17 pathways seem to be the most promising avenues. New achievements in the knowledge of pSS pathophysiology are necessary in order to try to simultaneously predict the predominant pathogenic pathway, the kind of patients at major risk to develop a more severe disease, and the appropriate biological therapy to use.

The cumulative number of micro-haemorrhages and micro-thromboses in nailfold videocapillaroscopy is a good indicator of disease activity in systemic sclerosis: a validation study of the NEMO score

BackgroundSome abnormalities in nailfold videocapillaroscopy (NVC), such as the presence of micro-haemorrhages (MHEs), micro-thromboses (MTs), giant capillaries (GCs) and reduction in the number of capillaries (nCs), suggest a disease activity (DA) phase in systemic sclerosis (SSc). In a previous paper, we showed that the number of micro-haemorrhages and micro-thromboses (the so-called NEMO score) was the NVC feature more closely associated with DA. The present study was aimed at validating the NEMO score as a measure of DA in patients with SSc.MethodsTwo cohorts of 122 and 97 patients with SSc who were referred to two different rheumatology units, one in Milan and one in Naples, respectively, constituted the validation cohorts. The NEMO score, the total number of GCs and the mean nCs per digit were the parameters defined in each patient by eight-finger NVC. An expert operator analysed the NVCs in each of the participating units. The European Scleroderma Study Group (ESSG) index was used to define the DA level in each patient at the time of NVC examination.ResultsThe NEMO score was the NVC parameter more strictly correlated with the ESSG score in both the Milan and Naples cohorts (p < 0.0001), and it was the only one among the NVC variables that gave a significant contribution in a logistic model where the ESSG score represented the dependent variable. ROC curve analysis confirmed that the NEMO score had the best performance in measuring DA. The AUC of the NEMO score was significantly greater than the AUCs obtained by plotting the sensitivity and specificity of the number of GCs and the mean nCs (p < 0.0001 in all cases). The NEMO score values that showed the best sensitivity-specificity balance in capturing patients with a relevant DA level were slightly higher in the Naples cohort than in the Milan cohort.ConclusionsThis study confirms that the presence of a certain number of MHEs and MTs in NVC may be considered a strong warning signal of a current phase of DA in patients with SSc.

State of the art in interstitial pneumonia with autoimmune features: a systematic review on retrospective studies and suggestions for further advances

The term interstitial pneumonia with autoimmune features (IPAF) has been proposed to define patients with interstitial lung disease (ILD) associated with autoimmune signs not classifiable for connective tissue diseases (CTDs). This new definition overcomes previous nomenclatures and provides a uniform structure for prospective studies through specific classification criteria. This work evaluates the characteristics of IPAF patients reported in the literature, to highlight potential limits through a comparative analysis and to suggest better performing classification criteria. Four retrospective studies on the IPAF population have been considered. The study subjects differed in age, sex, smoking habit, ILD pattern and outcomes. Another important difference lies in the diverse items considered in the classification criteria. The retrospective design of the studies and the absence from some of them of a rheumatologist clearly involved in the diagnosis may have influenced the data, but current IPAF criteria seem to include a rather heterogeneous population. To overcome these discrepancies, this review suggests a limitation in the use of single items and the exclusion of extremely specific CTD criteria. This should avoid the definition of IPAF for those diseases at different stages or at early onset. The investigation of a functional or morphological cut-off of pulmonary involvement would be useful. IPAF retrospective cohorts show numerous differences between them. We propose some ideas to improve IPAF criteria http://ow.ly/eubC30jlGJO

Is there any role for thoracic ultrasound for interstitial lung disease underlying rheumatologic conditions? Reply

We appreciate the interest of Tinti and colleagues [1] in our recent article about the role of thoracic ultrasound (TUS) in interstitial lung disease (ILD) associated with connective tissue diseases (CTDs) [2]. These authors offer their personal perspective based on the previous work conducted in their Institution. By stating that TUS ‘‘can provide potentially useful information regarding the structural and functional changes provoked by ILD, even in the early stages of the disease’’, they agree with our analysis of the scientific literature. However, they disagree about the relevance of the specific information that can be sampled by TUS. In particular, they are concerned that counting ‘‘Blines’’ may be inaccurate in assessing ILD in CTD, and they propose measuring pleural line thickness instead on the basis of its good sensitivity and specificity reported in their study of patients with systemic sclerosis (SSc) [3]. Nonetheless, we are in disagreement with Tinti and colleagues, because there is ample evidence that B-lines assessment is very accurate in identifying ILD in CTDs, including two studies with a sensitivity of 100%, which is particularly useful for the purposes of screening and monitoring of patients with CTDs [2]. That is why the assessment of B-lines has been proposed as an important TUS parameter when investigating for ILD patients with CTDs [4]. In any case, accuracy in identifying ILD in CTDs by B-lines assessment may be improved depending on its cutoff value. In our analysis, we discussed the paper by Buda and colleagues in which a cut-off value of C4 B-lines was considered of adequate specificity for the purpose of diagnosing ILD in patients with CTDs [5], but it is possible that a different cut-off value in B-lines numbers can further improve diagnostic separation from conditions like cardiogenic or noncardiogenic pulmonary edema, acute lung injury/acute respiratory distress syndrome, interstitial pneumonia, pneumonitis, as well as pleurisy, lung contusion, pulmonary infarction, atelectasis, and lung cancer. Indeed, it was already emphasized in our paper the importance of establishing a cut-off value by standardizing the technique in large series of patients with CTDs. As noted by Tinti and colleagues ‘‘the evaluation process of B-lines is at best semi-quantitative, because the method is more of a subjective overview than an actual measurement’’, and this is acknowledged. However, this is not necessarily a limitation. The same argument could be raised for nailfold capillaroscopy, but methods of semiquantitative and quantitative evaluation provide similar results. Obviously, we are in agreement with Tinti and colleagues that TUS is ‘‘easy to repeat and this makes it an ideal method for monitoring the ‘evolution of the disease and patients’ response to treatment’’, and ‘‘...could represent the complementary diagnostic approach [for high resolution chest tomography]’’, as already mentioned in our paper. In conclusion, in the light of the available data and depending on the intended purpose for TUS in ILD, several authors now recognize the assessment of B-lines as a promising ultrasonographic parameter. Future studies will be needed to confirm and validate the usefulness of new & Domenico Sambataro d.sambataro@hotmail.it

Emerging potential for bisphosphonates in the treatment of axial spondyloarthritis

journals.sagepub.com/home/taj 1 Ankylosing spondylitis is a chronic inflammatory condition that typically affects the joints of the spine and is characterized by inflammatory low back pain (LBP). Over time, progression of the joint inflammation leads to ankylosis of the sacroiliac joints and spine. Early diagnosis of ankylosing spondylitis is crucial for prognosis: although it is well known that nonsteroidal anti-inflammatory drugs (NSAIDs) and tumor necrosis factor α (TNFα) blockers in general fail to arrest the development of ankylosis in ankylosing spondylitis,1 recent studies have raised the possibility that treatment of early ankylosing spondylitis with TNFα antagonists can reduce radiographic progression.2

Darier's disease and rheumatoid arthritis: a new association and a revision of the literature

Dear Editor, Darier’s disease (DD), also known as Darier–White’s disease or keratosis follicularis, is a rare autosomal genodermatosis, characterized by an altered differentiation and acantholysis of keratinocytes. Currently, some reports describe the co-occurrence of this skin disorder with different rheumatic diseases, suggesting a possible pathogenetic link between DD and autoimmunity. Here, we want to introduce our case that could represent, to our knowledge, the first possible case of DD associated with rheumatoid arthritis (RA). A 45-year old woman came to our attention for the onset of persistent articular pain, previously identified as RA. In anamnesis, she reported in puberty a histological diagnosis of DD. Physical examination showed swelling and pain of the wrists and right knee, together with the presence of small keratotic papules, localized in the scalp, retroauricular folds, back, arms and legs (Fig. 1). Laboratory findings confirmed the rheumatologic diagnosis, showing the presence of elevated inflammatory indices (erythrocyte sedimentation rate 97 mm/h, C-reactive protein 26.4 mg/dL, normal 3) and a mild anemia. Rheumatoid factor and anti-cyclic citrullinated peptide antibodies were highly positive. On the basis of the elevated disease activity (Disease Activity Score of 28 joints – CPR 5.24), treatment with leflunomide and nonsteroidal anti-inflammatory drugs (NSAIDs) (i.e., diclofenac) was promptly started, with initial improvement, lasting for 6 months. With the succeeding worsening of articular symptoms, associated with highly active scores, defined by disease activity indices, a therapy with certolizumab pegol was initiated, determining clinical articular improvement without response of the cutaneous lesions, that underwent regression with NSAIDs. DD is a rare skin disorder, affecting both sexes and all ethnic groups, with a prevalence ranging from 1 in 30 000 to 1 in 50 000 and onset in puberty. Penetrance is complete with an extreme variability in terms of expression within family components. The responsible gene is ATP2A2, found on the long arm of the 12th chromosome (12q23–24), which encodes SERCA2 (isoform of Ca ATPase of the sarcoplasmic reticulum). Clinically, the altered Ca pump leads to the formation of greasy keratotic papules, skin-colored or yellowbrown, isolated or confluent in plaques, localized in seborrheic areas of the upper trunk, folds, neck, and scalp. Nail abnormalities can also be associated, consisting in red longitudinal stripes, splitting and a V-shaped nick at the free margin of the nail. These findings can simulate the appearance of psoriatic arthritis or SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis). Moreover, DD is associated with neuropsychiatric abnormalities that include epilepsy, Figure 1 Keratotic papules present in the patient, localized in the back, arms, and legs.

Reply to J. Magalon et al.

*U.O.C. Day Hospital Reumatologia, Ospedale G. Pini, Milano, Italy †U.O.S. Chirurgia Vascolare, Ospedale G. Pini, Milano, Italy ‡U.O. Clinica Medica, Dipartimento di Medicina Interna, Ospedali Riuniti, Ancona, Italy §Centro di Riferimento per le Malattie Autoimmuni Sistemiche, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milano, Italy ¶Dipartimento Medicina Interna e Reumatologia, Campus Biomedico, Roma, Italy #Laboratorio Emodinamica Periferica Interventistica, Humanitas Gavazzeni, Bergamo, Italy **Servizio di Reumatologia, Istituto San Giuseppe, Anzano del Parco, Como, Italy

SAT0471 Autologous Hematopoietic Stem Cell Transplantation in Rapidly Progressive Systemic Sclerosis is More Effective Than Conventional Therapies in Inducing Disease Remission and Prologing Survival

Background Autologous haematopoietic stem cell transplantation (AHSCT) has shown to be an effective therapeutic option to prolong survival of patients (pts) suffering from rapidly progressive diffuse cutaneous systemic sclerosis (rp-dcSSc). Objectives This study was aimed at retrospectively comparing the disease outcome of pts with rp-dcSSc treated with AHSCT to that of age-, and sex-matched group of clinically similar pts selected from our cohort and treated with conventional therapies. Methods Eighteen pts (5 M, 13F; median age 40, 20-62 yrs) that underwent AHSCT were compared to 36 age- and sex-matched pts (10 M, 26 F; median age 44, 19-62 yrs), all of them suffering from rp-dcSSc. At the starting evaluation point the two groups were also exactly comparable for disease-duration and clinical findings, in term of skin involvement (mRSS), DLCO as % of predicted value and disease activity (ESSG scoring system). AHSCT was performed by mobilisation with cyclophosphamide (CTX) and G-CSF, selection of CD34+ cells and conditioning regimen with CTX and rabbit ATG. Twenty-five pts in the control group received 6 monthly pulses of intravenous CTX (750mg/m2), 11 received steroids, DMARDS (Methotrexate and Azathioprine) and vasoactive therapies (noCTX). The clinical course in AHSCT and control groups was evaluated from time 0 to 5 years by using Kaplan Meyer survival curves, computing the Hazard Ratio (HR) and Chi square distribution. Results Results of the survival curve analysis of different groups, expressed as HR (95%CI) are reported in the table.Table 1 Parameters AHSCT vs all controls AHSCT vs CTX treated controls AHSCT vs noCTX treated controls CTX vs noCTx treated controls Death HR 14,0264 (95% CI 6,1–32,4) HR 11,7432 (95% CI 4,8–28,5) HR 21,2597 (95% CI 6,1–74,4) HR 1,8104 (95% CI 0,5–6,2) mRss <14 HR 2,9210 (95% CI 1,3 to 6,3) HR 2,4752 (95% CI 1,1–5,6) HR 4,6148 (95% CI 1,9–11,5) HR 1,8644 (95% CI 0,9–3,8) DLCO >45% HR 6,0225 (95% CI 2,9–12,6) HR 3,0830 (95% CI 1,2–8,0) HR 7,7912 (95% CI 3,4–17,8) HR 0,3957 (95% CI 0,1–1,1) ESSG <3 HR 7,8532 (95% CI 2,3–21,1) HR 7,7759 (95% CI 2,8–21,7) HR 8,0337 (95% CI 2,5–25,8) HR 1,0332 (95% CI 0,4–2,5) Conclusions This retrospective study confirms that AHSCT approach is more effective to induce a longer survival (p=0.0004), and shows that is also able to more rapidly reduce the mRss (p<0.0001), disease activity (p<0.0001), and preserve lung function (p=0.0004), with respect to conventional therapies in rp-dcSSc. Disclosure of Interest None declared