Giacomo Maria Guidelli

Mechanisms of action of spa therapies in rheumatic diseases: what scientific evidence is there?

Spa therapy represents a popular treatment for many rheumatic diseases. The mechanisms by which immersion in mineral or thermal water or the application of mud alleviates suffering in rheumatic diseases are not fully understood. The net benefit is probably the result of a combination of factors, with mechanical, thermal and chemical effects among the most prominent ones. Buoyancy, immersion, resistance and temperature all play important roles. According to the gate theory, pain relief may be due to the pressure and temperature of the water on skin; hot stimuli may influence muscle tone and pain intensity, helping to reduce muscle spasm and to increase the pain threshold. Mud-bath therapy increases plasma β-endorphin levels and secretion of corticotrophin, cortisol, growth hormone and prolactin. It has recently been demonstrated that thermal mud-pack therapy induces a reduction in the circulating levels of prostaglandin E2 (PGE2), leukotriene B4 (LTB4), interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α), important mediators of inflammation and pain. Spa therapy has been found to cause an increase in insulin-like growth factor-1 (IGF1), which stimulates cartilage metabolism, and transforming growth factor-β (TGF-β). There is also evidence of the positive action of mud-packs and thermal baths on the oxidant/antioxidant system, with a reduction in the release of reactive oxygen (ROS) and nitrogen (RNS) species. Overall, thermal stress has an immunosuppressive effect. Many other non-specific factors may also contribute to the beneficial effects observed after spa therapy in some rheumatic diseases, including effects on cardiovascular risk factors, and changes in the environment, pleasant surroundings and the absence of work duties.

Intravenous immunoglobulins and antiphospholipid syndrome: How, when and why? A review of the literature

The antiphospholipid syndrome (APS) is defined by the occurrence of venous and arterial thromboses and recurrent fetal losses, frequently accompanied by a moderate thrombocytopenia, in the presence of antiphospholipid antibodies (aPL), namely lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or anti-β2 glycoprotein-I (β2GPI) antibodies. The current mainstay of treatment for thrombotic APS is heparin followed by long-term anticoagulation, while in obstetric APS, the accepted first-line treatment consists in low-dose aspirin (LDA) plus prophylactic unfractionated or low-molecular-weight heparin (LMWH). Recently, new emerging treatment modalities, including intravenous immunoglobulins (IVIG), have been implemented to manage APS refractory to conventional therapy. The objective of this review is to summarize the currently available information on the IVIG therapy in APS, focusing on the use of IVIG in the obstetric form, CAPS and on primary or secondary thromboprophylaxis. We analyzed 35 studies, reporting the effects of IVIG in APS patients, and we discussed their results. IVIG in obstetric APS seem to be very useful in selected situations (patients not responsive to the conventional treatment, concomitant autoimmune manifestations or infections or patients in whom anticoagulation is contraindicated). IVIG treatment represents an important component of the combination therapy of CAPS and they could be useful, in addition to the standard therapy, to prevent recurrent thrombosis in APS patients refractory to conventional anticoagulant treatment. Anyway, in some cases we also found controversial results that claim the need of further well-designed studies to definitely state the efficacy and tolerability of IVIG in CAPS, obstetric and non-APS.

Gemcitabine, oxaliplatin, levofolinate, 5-fluorouracil, granulocyte-macrophage colony-stimulating factor, and interleukin-2 (GOLFIG) versus FOLFOX chemotherapy in metastatic colorectal cancer patients: the GOLFIG-2 multicentric open-label randomized phase III trial.

The GOLFIG-2 phase III trial was designed to compare the immunobiological activity and antitumor efficacy of GOLFIG chemoimmunotherapy regimen with standard FOLFOX-4 chemotherapy in frontline treatment of metastatic colorectal cancer (mCRC) patients. This trial was conceived on the basis of previous evidence of antitumor and immunomodulating activity of the GOLFIG regimen in mCRC. GOLFIG-2 is a multicentric open/label phase III trial (EUDRACT: 2005-003458-81). Chemo-naive mCRC patients were randomized in a 1:1 ratio to receive biweekly standard FOLFOX-4 or GOLFIG [gemcitabine (1000 mg/m2, day 1); oxaliplatin (85 mg/m2, day 2); levofolinate (100 mg/m2, days 1–2), 5-fluorouracil (5-FU) (400 mg/m2 in bolus followed by 24 h infusion at 800 mg/m2,days 1–2), sc. GM-CSF (100 &mgr;g, days 3–7); sc. aldesleukin (0·5 MIU bi-daily, days 8–14 and 17–30)] treatments. The study underwent early termination because of poor recruitment in the control arm. After a median follow-up of 43.83 months, GOLFIG regimen showed superiority over FOLFOX in terms of progression-free survival [median 9·23 (95% confidence interval (CI), 6·9–11.5) vs. median 5.70 (95% CI, 3.38–8.02) months; hazard ratio (HR): 0.52 (95% CI, 0.35–0.77), P=0·002] and response rate [66.1% (95% CI, 0.41–0.73) vs. 37·0% (95% CI, 0.28–0.59), P=0.002], with a trend to longer survival [median 21.63 (95% CI, 18.09–25.18) vs. 14.57 mo (95% CI, 9.07–20.07); HR: 0·79 (95% CI, 0.52–1.21); P=0.28]. Patients in the experimental arm showed higher incidence of non-neutropenic fever (18.5%), autoimmunity signs (18.5%), an increase in the number of monocytes, eosinophils, CD4+ T lymphocytes, natural killer cells, and a decrease in immunoregulatory (CD3+CD4+CD25+FoxP3+) T cells. Taken together, these findings provide proof-of-principle that GOLFIG chemoimmunotherapy may represent a novel reliable option for first-line treatment of mCRC.

Granulomatosis with polyangiitis and intravenous immunoglobulins: A case series and review of the literature

Granulomatosis with polyangiitis, formerly known as Wegeners granulomatosis or disease, is a systemic, necrotizing small-vessel vasculitis, belonging to the group of anti-neutrophil cytoplasm antibody vasculitis. The therapeutic strategy includes, in most cases, corticosteroids associated, at least in severe forms of the disease, with immunosuppressive agents: cyclophosphamide and rituximab to induce remission, methotrexate, azathioprine and mycophenolate mofetil to prevent relapses. Intravenous immunoglobulins represent an alternative adjuvant therapy. We described 5 cases of patients with granulomatosis with polyangiitis treated with monthly high-dose intravenous immunoglobulins (500mg/kg/daily for 3 consecutive days for 9months). No patients experienced adverse reactions, and 4 patients (80%) achieved a complete remission after 9 courses of this therapy, which was maintained also 3months later, although we are unable to determine whether improvement in outcomes was a direct result of the IVIG. We also discussed the beneficial effects of intravenous immunoglobulins in patients suffering from granulomatosis with polyangiitis, reporting the previously published data.

Fibromyalgia syndrome and spa therapy: myth or reality?

Fibromyalgia syndrome (FS) is a common musculoskeletal disorder characterized by otherwise unexplained chronic widespread pain, a lowered pain threshold, high tender point counts, sleep disturbances, fatigue, headache, irritable bowel syndrome, morning stiffness, paraesthesias in the extremities, often psychological distress and depressed mood. Consequently, FS has a negative impact on working capacity, family life, social functioning and quality of life. Because of unknown etiology and not clearly understood pathogenesis, there is no standard therapy regime for FS. A variety of medical treatments, including antidepressants, opioids, analgesic or non-steroidal anti-inflammatory drugs, sedatives, muscle relaxants and antiepileptics, have been used to treat FS. Currently, no pharmacological treatment for FS is consistently successful. According to recent guidelines, the optimal treatment of FS requires a multidisciplinary approach with a combination of non-pharmacological and pharmacological treatment modalities. Spa therapy is a popular treatment for FS in many European countries, as well as in Japan and Israel. However, despite their long history and popularity spa treatments are still the subject of debate and their role in modern medicine is still not clear. The objective of this review is to summarize the currently available information on clinical effects and mechanism of action of spa therapy in FS. We also provide some suggestions for further development in this area.

What about strontium ranelate in osteoarthritis? Doubts and securities.

Abstract Osteoarthritis (OA) is the most common disabling joint disease worldwide and its treatment is based on a combination of non-pharmacological and pharmacological modalities. Commonly prescribed OA medications include symptomatic drugs (non-steroidal anti-inflammatory drugs, analgesics, locally administered corticosteroids, viscosupplementation) and new compounds that are potentially able to reduce or stop the disease progression, called “Disease Modifying Osteoarthritis Drugs (DMOADs)”. Strontium ranelate (SR) is an anti-osteoporotic treatment that increases bone formation, while decreasing bone resorption and it potentially acts as a new DMOAD. The objective of this review is to summarize the currently available information on clinical effects and mechanism of action of SR in OA. We have examined two post hoc analysis conducted on the large, randomized Treatment of Peripheral Osteoporosis study and the double-blind, randomized, controlled trial about SR in knee OA. Furthermore, we analyzed three studies in animal models and two in vitro experiments to better understand the mechanism of action of SR in OA. The available data demonstrate that SR could be considered a new promising symptomatic and disease-modifying agent in the treatment of OA and was safe and well tolerated. Additionally, there is a need for further investigations to establish the optimal dosage and to better clarify the mechanism of action of SR in OA.

Dactylitis as a first manifestation of arthritis associated with hidradenitis suppurativa

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Phase Ib study of poly-epitope peptide vaccination to thymidylate synthase (TSPP) and GOLFIG chemo-immunotherapy for treatment of metastatic colorectal cancer patients

ABSTRACT Thymidylate synthase (TS) is a tumor-associated enzyme critical for DNA replication and main 5′-fluorouracil (5′-FU) target. TSPP/VAC1 is a multi-arm trial phase-Ib trial program aimed to investigate the toxicity and biomodulatory activity of a poly-epitope-peptide vaccine to TS (TSPP) in cancer patients (pts). Here, we present the results of the TSPP/VAC1/arm C trial aimed to evaluate TSPP in combination with chemo-immunotherapy in pretreated metastatic colo-rectal cancer (mCRC) pts. Twenty-nine pts, 14 males and 15 females, received poly-chemotherapy with gemcitabine [GEM; 1,000 mg/sqm, day-1], oxaliplatin [OX; 80 mg/sqm, day-2], levofolinate [100 mg/sqm, days 1–2], bolus/infusional 5′-FU [400 mg/800 mg/sqm, days 1–2], sargramostim [50 μg, days 3–7/q30], and interleukin-2 [sc. 0.5 MIU twice a day, days 8–14/18–30] [GOLFIG-regimen]. Seventeen pts received sc. TSPP injections at escalating dosage [3 pts, 100 µg (DL-1); 3 pts, 200 µg (DL-2) and 11pts, 300 µg (DL-3)] one week after each chemotherapy cycle (concomitant module), while 10 out 12 pts received TSPP (300 µg) after 12 GOLFIG courses [dose level (DL)-0] (sequential module). TSPP MTD was not achieved. Adverse events consisted in swelling/erythema at injection sites (17 cases), G1–2 haematological (16 cases) and gastro-enteric events (12), fever, rhinitis, conjunctivitis, and poly-arthralgia and rise in auto-antibodies [ANA, ENA, c-ANCA, p-ANCA in the DL1–3 pts]. Both treatment-modules showed immunomodulating and antitumor activity (disease-control-rate, DL1–3 and DL0 were 70.6% and 83.3%, respectively) with a better survival recorded in the second group [median OS DL1–3 vs. DL0 = 8 vs. 16 mo, p = 0.049]. The promising long-term survival produced by the sequential treatment module deserves further phase II evaluation.

The effects in vitro of TNF-α and its antagonist 'etanercept' on ejaculated human sperm.

Tumour necrosis factor (TNF)-α is primarily involved in the regulation of cell proliferation and apoptosis; in addition it possesses pro-inflammatory properties. Anti-TNF-α strategies involve either administration of anti-TNF-α antibody or soluble TNF receptor to mop up circulating TNF-α. Etanercept, a recombinant human TNF-α receptor, was found to be effective in the treatment of rheumatoid arthritis. The impact of TNF-α inhibitors on human fertility is of notable interest. This in vitro study investigated the effect of different concentrations of TNF-α and etanercept used alone or in combination on sperm viability, motility, mitochondrial function, percentage of apoptosis and chromatin integrity in swim-up selected human spermatozoa. A negative effect of TNF-α (300 and 500ng mL-1) and etanercept (from 800µg mL-1 to 2000µg mL-1) individually on sperm viability, motility, mitochondrial function, percentage of apoptotic spermatozoa and sperm DNA integrity was demonstrated. However, at concentrations of 100 and 200µg mL-1, etanercept can block, in a significant way, the toxic effects of TNF-α (500ng mL-1) on studied sperm characteristics. Our results confirm that TNF-α has a detrimental effect on sperm function and suggest, for the first time, that etanercept may counteract the in vitro toxic action of TNF-α. This data appears to be quite promising, although further studies, both in vivo and in vitro, are needed to understand the exact mechanism of action of TNF-α and TNF-α antagonists on sperm function.

Punch biopsy for fat tissue collection in amyloidosis: is it time to stop needle aspiration?

SIR, Amyloidosis is a heterogeneous group of diseases that share the deposition of amyloid fibrils in organs and tissues, with the same characteristic cross-b-sheet secondary structure, independent of their protein primary structure. More than 30 unrelated autologous proteins can produce systemic amyloidoses, either localized or systemic. The various forms differ in pathogenesis and prognosis, but usually show overlapping clinical manifestations, making their differentiation on clinical grounds very difficult. Precise amyloid typing is crucial for adequate treatment of patients because the various forms require different approaches, which can range from autologous stem cell transplantation in amyloid light-chain (AL) amyloidosis to liver transplantation in transthyretin amyloidosis. The diagnosis and classification are based on histological demonstration of amyloid deposits and characterization of the amyloid precursor [1, 2]. Rectal biopsy has traditionally been the recommended method of screening for amyloidosis. However, since 1973, abdominal fat pad aspiration by fine needle has superseded rectal biopsy as the simplest, fastest and most acceptable way to screen for amyloid, when a systemic form is suspected, being a convenient alternative to organ biopsy [3, 4]. The resulting tissue smear is examined by polarized light microscopy after Congo red staining, in order to detect the presence of amyloid. The second step is to identify the amyloidogenic protein, in order to unequivocally establish the type of amyloidosis. Its sensitivity ranges between 54% and 82%. It can be done at outpatient clinic and requires no technical expertise [4]. Abdominal fat tissue can be aspirated with a 16gauge needle connected to a 10-ml syringe [5]. Although it is safe and reliable, fat aspiration by needle does not yield enough tissue for evaluation in some cases, and its low sensitivity could be related to the possible impact of the size of the needle used for aspiration [6]. Furthermore, there is a need for multiple aspirations (at least three) from different places, especially in patients with a thin abdominal wall. Smith et al. [7] first described in 1986 the usefulness, simplicity and reliability of using a 3.0 mm punch biopsy for collecting skin plus s.c. fat, needed for gas chromatographic analysis of fatty acids. Bogov et al. [8] in 2008 described their positive experience of s.c. fat biopsy to diagnose amyloidosis, made by scalpel and not by punch. We describe a single-centre experience of s.c. fat biopsy, performed by punch. Between March 2012 and December 2014, we performed 138 biopsies at outpatient clinic. All patients (84 female and 54 male, mean age 56.2 years) required such a diagnostic procedure, in order to exclude amyloidosis secondary to various rheumatological conditions, including RA, Behçet’s syndrome and autoinflammatory diseases. In addition, the reliability for amyloid detection in fat samples obtained by punch biopsy was evaluated in comparison with fat specimens obtained from May 2010 to March 2012 by fine needle aspiration technique at our clinic. The biopsy site was prepared with three betadine scrubs and covered with a fenestrated sterile drape. The dermis at the biopsy site (at the right anterior axillary line at the level of the umbilicus) was infiltrated with 0.5 ml of 1% lidocaine followed by injection of 4 ml in the very superficial layers of adipose tissue immediately below the skin (no more than 1 cm deep). Punch biopsy was performed using a circular blade (3.0 mm in diameter) attached to a pencil-like handle. The instrument was rotated down through the epidermis and dermis and into the s.c. fat (Fig. 1A). Punch biopsy yields a cylindrical core of tissue that requires gentle handling (usually with a needle) to prevent a crush artefact at the pathological evaluation. The biopsy site was closed with a single absorbable suture (Vicryl 3-0). Because linear closure was performed on the circular defect, stretching the skin before performing the punch biopsy allows the relaxed skin defect to appear more elliptical and makes it easier to close. The skin was stretched perpendicular to the relaxed skin tension lines, so that the resulting elliptical wound and closure were parallel to these skin tension lines. This modified method does not require any special preparations, materials or consumables. It is easily performed and can be applied in all conditions, including patients with disturbances of coagulation. It generally produces only a minimal scar, and no patients experienced adverse events related to the biopsy; only mild bruising was observed in few patients. We did not observe any site infection; only seven patients reported local transient (<48 h) paraesthesia. The fat tissue obtained by the afore-mentioned procedure is significantly richer in volume in comparison with the fat obtained by needle aspiration (Fig. 1B); in addition, this procedure by punch is able to provide an amount of histologically wellpreserved fat tissue. All of the samples obtained by punch biopsy (n = 138) were suitable for pathological evaluation, compared with 74 of 96 samples (78%) obtained by fine needle aspiration. In conclusion, punch biopsy could represent a quick, cheap and simple procedure for fat collection for identification of amyloid deposits.