1Nuclear Medicine Unit, Department of Medical‐Surgical Sciences and of Translational Medicine, Faculty of Medicine and Psychology, “Sapienza” University of Rome, Rome, Italy
2Nuclear Medicine, ClinicaColsanitas, Bogotà, Colombia
3Endocrinology Unit, “Regina Apostolorum” Hospital, Albano (Rome), Italy
4.4.5
introduction
Inflammatory diseases are a heterogeneous class of diseases characterized by chronic inflammation of the target organ, often relapsing, invalidating, and requiring lifelong treatment. The so‐called aseptic chronic inflammatory dis
eases include autoimmune diseases, graft rejection, sarcoidosis, vasculitis, ath
erosclerosis, and some degenerative diseases. In these patients, it is very important to achieve specific immune suppression to extinguish the immune process with the aim of stopping the disease, preventing or delaying complica
tions, and avoiding disease relapse. It is important that while attempting to improve the quality of life of these patients by means of anti‐inflammatory drugs, side effects are reduced to a minimum via the use of specific immune therapies that block as selectively as possible the pathologic mechanisms responsible for the disease.
New therapeutic options are being developed for specific targeted therapies.
Several trials are being performed to assess the efficacy and safety of new approaches. All of them, however, rely mostly on the clinical assessment of the patients to evaluate the effect of treatment. It would be important to use an objective and reliable method to highlight directly the immune process underlying the individual disease; specific diagnostic tests, furthermore, may allow the selection of patients to be treated.
Nowadays, nuclear medicine techniques are not often used for the diagnosis of chronic inflammatory diseases but greatly contribute to the management and prog
nosis of the disease. Most importantly, somatostatin receptor scintigraphy (SRS) has been proposed for the evaluation of the state of activity of some inflammatory dis
eases and to early evaluate therapy efficacy. This is particularly important because new molecular therapeutic biological agents that specifically target and block inflammatory reactions are continuously being developed. The referring physician not only obtains information on the activity of the disease but also on the nature of the process and can, therefore, decide which treatment to start, when to start it, and when to stop it or modify it.
somAtostAtin receptor expression in inflAmmAtory diseAses
Many hormones and some neuropeptides and neurotransmitters play a key role in regulating lymphoid cells; somatostatin, in particular, is involved in numerous regu
lating mechanisms of cell activities in the immune system. The expression of somato
statin receptors in the thymus in man has prompted the hypothesis that this hormone participates in the maturation process of T lymphocytes.
Somatostatin receptors are expressed on both activated lymphocytes and inflamed vascular endothelium. SRS holds important information not only by demonstrating the presence of inflammation but also by providing a rationale, in positive patients, for the use in selected cases, of unlabelled somatostatin for the treatment of the
STUDY OF SJÖGReN SYNDROMe BY SRS 155
disease. The expression of receptors for somatostatin has been investigated in patients with autoimmune diseases and cancer [1].
Hyperexpression of the somatostatin receptor (SSTR) has been found in intestinal samples from patients with active ulcerative colitis and Crohn’s disease. SSRs were localized in intramural veins and were not detected in noninflamed control intestine [2]. SSRs were reported in vitro in patients with active rheumatoid arthritis [3].
SRS is applicable in imaging of chronic inflammation but is unsuitable for visual
ization of acute infectious diseases [4]. Ten Bokum et al. showed in 2002 accumulation of In‐111 DTPA‐octreotide in the thymus and the pituitary of normal Balb/c mice and of nonobese diabetic mice, a strain prone to autoimmune type 1 diabetes. They were unable, however, to show any uptake in the inflamed pancreas of prediabetic animals [5].
Radiolabeled somatostatin analogues have been extensively used for the study of neuroendocrine tumors [6], particularly in gastroenteropancreatic tumors, where the presence of receptors for somatostatin has been demonstrated [7]. The most commonly used analogue is 111In‐[d‐Phe1]‐pentetreotide (OctreoScan), a small octapeptide that binds with high affinity to the somatostatin type 2 receptor expressed on the cell membrane of the target tissues. It has no side effects. Several analogues have been synthetized and are currently used in routine clinical practice.
A recent analogue that has been used in autoimmune diseases is 99mTc‐HYNIC‐
[d‐Phe1,Tyr3]‐octreotide (99mTc‐HYNIC‐TOC), which has extensively been used in neuroendocrine tumors and in inflammatory diseases [8]. 99mTc‐Depreotide is another analogue that has been used to localize sites of inflammation in patients with viral myocarditis [9] and in patients with bone infection [10, 11].
study of sJÖgren syndrome by srs
Sjögren syndrome (SS) is characterized by dry mouth and dry eyes (sicca syndrome) as a result of autoimmune destruction of salivary and lacrimal glands. Specific auto
antibodies (anti‐SSA and anti‐SSB) are detectable in the peripheral blood, but the diagnosis of the disease is based on biopsy and/or salivary gland hypofunction as detected by Schirmer test (AeCG criteria). The role of salivary gland scintigraphy (scialoscintigraphy) is still a matter of debate and new imaging modalities are indeed required to demonstrate the presence of lymphocytic infiltration in the salivary glands.
New immunological treatments are being tested for SS (infliximab, rituximab), and it would be useful to have a diagnostic test capable of detecting infiltrated glands that could be used for therapy selection and monitoring (Fig. 4.4.5.1).
A recent study has described the use of the new somatostatin analogue 99mTc‐
HYNIC‐Tyr(3)‐octreotide for the diagnosis of the state of activity in patients with rheumatoid arthritis and secondary SS before and after treatment with infliximab.
Results showed that inflamed parotid glands could be diagnosed by this radiophar
maceutical. Inflamed joints were also detected in patients with active rheumatoid arthritis [8]. Interestingly, after treatment with infliximab, normalization of the uptake in most inflamed joints was noted but not in salivary glands, probably reflecting the different nature of the two diseases.
study of thyroid diseAses by srs
Autoimmune thyroid diseases, including Graves’ disease, primary myxedema, and Hashimoto’s thyroiditis, appear related in certain aspects of their pathogenesis and clinical course. evidence of humoral immunity is provided in all of these disorders by the presence of antibodies against thyroid peroxidase (formerly known as micro
somal antigen) and often against thyroglobulin. Antibody titles tend to be highest in Hashimoto’s disease and lowest in primary hypothyroidism at the time it is diag
nosed. More specific to Graves’ disease are circulating autoantibodies that are capable of binding to the thyroid‐stimulating hormone receptor (TSHr) on the sur
face of thyroid cells and stimulate cell growth and hormone production. Graves’
disease, primary myxedema, and Hashimoto’s thyroiditis all share evidence of cell‐
mediated immunity against thyroid antigens and are characterized by a varying degree of infiltration by lymphocytes and plasma cells. The infiltrating cells collect in aggregates, forming lymphoid follicles with germinal centers [12, 13].
exophthalmos is a frequent manifestation of Graves’ disease that may lead to severe complications. It is caused by muscle hypertrophy and lymphocytic infiltration of the retro‐orbital space, which may eventually turn into fibrosis. exophthalmos is usually treated with corticosteroids and/or cyclosporin or by local X‐ray therapy. It would be extremely important to be able to diagnose the state of activity of the disease and to differ
entiate between active infiltration and fibrosis because of the difference in their treatment.
Current diagnosis of thyroid autoimmunity is based on the detection of auto
antibodies (anti‐TSHr, anti‐TPO, and anti‐TG) and clinical signs and symptoms.
figure 4.4.5.1 SRS in a patient with Sjögren syndrome showing pathological uptake of labeled octreotide in major salivary glands. A minor uptake is also detectable in the thyroid gland. SRS—somatostatin receptor scintigraphy.
STUDY OF THYROID DISeASeS BY SRS 157
However, the relationship between autoantibodies and disease activity is still unclear, and it is generally believed that the activity of the autoimmune process is determined by the intensity of intrathyroidal lymphocytic infiltration. In vivo measurement of thyroid cellular infiltration, particularly in patients with undetectable serum thyroid autoantibodies, would be ideal for evaluating the disease activity, determining the need for therapy, and monitoring the efficacy of treatment (Fig. 4.4.5.2).
Forster and colleagues described the use of SRS in patients with Graves’ ophthal
mopathy and stressed the importance of SPeCT acquisition although with high inter
operator variability [14]. Very elegantly, Savastano and colleagues demonstrated the TSHr dependence of Graves’ ophthalmopathy in a patient with negative orbital SRS that became positive after the administration of recombinant TSH [15]. Krassas et al.
postulated in their review that the accumulation of the radionuclide is most probably due to the presence in the orbital tissue of activated lymphocytes bearing somato
statin receptors; alternative explanations are binding to receptors on other cell types (myoblasts, fibroblasts, or endothelial cells) and local blood pooling due to venous stasis by the autoimmune orbital inflammation [16].
Krassas et al. in 1997 used 111In‐octreotide scan to select patients with thyroid eye disease to be treated with lanreotide and to follow them up to evaluate the response to the treatment [17]. Diaz and colleagues in 1994 demonstrated, in 40 patients, the diagnostic value of somatostatin receptor scan not only for detecting and quantifying the inflammation severity in the retrocular space but in the follow‐up of the disease [18]. This same observation was made by Moncayo et al. who observed the inflam
mation in the retrobulbar tissue with 111In‐octreotide and used it for evaluating the response to the therapy [19]. Likewise, in another study, Colao et al. used
figure 4.4.5.2 SRS in a patient with autoimmune thyroid disease (Graves’ disease with mild orbitopathy) showing pathological uptake of labeled octreotide in the thyroid gland. No activity is detectable in salivary glands. SRS—somatostatin receptor scintigraphy.
111In‐octreotide to predict the clinical response to corticosteroid treatment in Graves’
ophthalmopathy and suggested using it as a useful approach to select patients for the proper treatment [20].
111In‐pentetreotide has been used in imaging of Graves’ disease, obtaining differ
ent contrasting results: a few studies have reported that this radiopharmaceutical accumulates in thyroid and in the retro‐orbital space in patients with exophthalmos and there is a positive correlation with the activity of disease [21, 22], in disagree
ment with other authors [23, 24]. Differences between authors might be explained by the possible mechanisms of accumulation of octreotide: uptake occurs in the early phases of Graves’ ophthalmopathy when active infiltration is present; in the later stage of the disease, there is fibroblastic activity with subsequent fibrosis in the retro‐
orbital region without expression of somatostatin receptors [25, 26].
A study was performed with 111In‐pentetreotide orbital scintigraphy on patients with severe ophthalmopathy caused by Graves’ disease, Hashimoto’s thyroiditis, and Means’ syndrome. Activated lymphocytes express somatostatin receptor during the active phase of the disease, permitting 111In‐pentetreotide scintigraphy. Authors con
cluded that 111In‐pentetreotide scintigraphy allows to select patients for octreotide therapy, which seems to be adequate in active, moderately severe thyroid eye disease, especially when it involves soft tissues [27–30].
Finally, Galuska et al. studied patients with Graves’ orbitopathy with 99mTc‐depre
otide with comparable results as for the other somatostatin analogues but showing excellent SPeCT images [31, 32].
study of sArcoidosis by srs
Octreotide is not suitable for the imaging of experimental abscesses [4], but SSRs were observed in vitro in multiple confluent granulomas in patients with active sarcoidosis. In this case, SSRs are not expressed on the surface of lymphocytes but are located in the areas containing epithelial cells (Fig. 4.4.5.3). In patients successfully treated with ste
roids with complete sclerosis of the granulomatous lesion, SSRs were not found. These studies are in agreement with studies in patients with tuberculosis [33]. A recent study by Lebtahi et al. compared the use of 111In‐pentetreotide to that of 67Ga‐citrate in patients with sarcoidosis, showing similar diagnostic accuracy [34]. A study by Migliore et al.
assessed the role of SRS using 99mTc‐HYNIC‐Tyr(3)‐octreotide in a patient with systemic sarcoidosis. The study showed that the technique was able to detect pulmonary and extrapulmonary localization of sarcoidosis. It was also possible to select the best therapeutic options. After treatment with infliximab, the patient showed normalization of the scan that correlated with improvement of clinical status [35]. Kwekkeboom et al., in a study of 46 patients with sarcoidosis, demonstrated uptake of 111In‐pentetreotide in 36 of 37 patients with known mediastinal, hilar, and interstitial disease. They postulated that somatostatin receptor imaging can demonstrate active granulomatous disease in patients with sarcoidosis [36]. The possible role of SRS in diagnosis, staging, and follow‐up of patients suffering from sarcoidosis was reviewed by Dalm et al. [37].
Shorr et al. used 99mTc‐depreotide in patients with sarcoidosis [38].
STUDY OF RHeUMATOID ARTHRITIS BY SRS 159
study of ibd by srs
Crohn’s disease is characterized by a chronic mononuclear cell infiltration of the intestinal wall and hypertrophy of local lymphoid tissues [39]. Immune erosion of the intestinal wall may lead to severe complications of the affected bowel such as stenosis and ulceration, which may require surgical resection. In over 70% of patients, relapse of the disease is noted within 1 year after the intervention. In the early relapse phase, the symptoms are infrequent and nonspecific, and conventional X‐ray exami
nations are negative. Since effective therapies are available, early diagnosis of the relapse might allow prompt initiation of therapy to prevent the onset of complications and the need for further surgical resection [40].
Hyperexpression of the somatostatin receptor has been found in intestinal samples from patients with active ulcerative colitis and Crohn’s disease. SSR were localized in intramural veins and were not detected in noninflamed control intestine [2]. The use of SRS in inflammatory bowel diseases (IBD) has been explored so far.
study of rheumAtoid Arthritis by srs
Rheumatoid arthritis is a chronic autoimmune disease characterized by severe short‐
and long‐term complications of the joints. Chronic mononuclear cell infiltration of the synovial membrane and subsequent erosion of cartilage and bone lead to joint ankylosis. The typical hemodynamic changes of acute inflammation and the persis
tence of the chronic infiltrate are both present.
figure 4.4.5.3 SRS in a patient with pulmonary sarcoidosis showing diffuse uptake in both lungs. Little activity is detectable also in the thyroid. SRS—somatostatin receptor scintigraphy.
figure 4.4.5.4 SRS in two patients with rheumatoid arthritis showing pathological uptake in knees (upper panel) and wrist and interphalangeal joints (lower panel). It is interesting to note that the left knee shows more uptake of labeled 99mTc‐HYNIC‐TOC compared to the right knee, indicating a different activity of the disease in the two joints. SRS—somatostatin receptor scintigraphy.
ReFeReNCeS 161
Specific and nonspecific signs of inflammation are normally used for the clinical diagnosis and follow‐up of the disease. Systemic treatment with anti‐inflammatory drugs (steroidal and nonsteroidal) is commonly employed for relief of symptoms and to delay disease progression. Treatment is usually lifelong and is accompanied by several side effects; local therapy is also used and has the advantage of higher local concentrations and fewer side effects. It would be very useful for the prevention of disease progression to diagnose affected joints before they become clinically evident, and local therapies could be applied before complications develop (Fig. 4.4.5.4).
Rheumatoid arthritis has been extensively studied by nuclear medicine techniques, and all radiopharmaceuticals tested showed accumulation in the inflamed joints [41].
SSRs were reported in vitro in patients with active rheumatoid arthritis [42]. Van Hagen et al. in 1994 in a sample of 14 patients with active AR and 4 with severe oste
oarthritis showed uptake in 76% of the painful and swollen joints of AR group positive findings [33].
conclusions
SRS has extensively been studied in several chronic inflammatory diseases and offers a valuable diagnostic tool that cannot be obtained by conventional diagnostic imaging. The radiopharmaceutical is commercially available, and the scintigraphy is easy to perform and may be used in all departments.
The main indications of SRS in inflammation are the selection of patients with active disease to be treated with immunomodulating therapies and monitoring of their efficacy, in particular where conventional diagnostic imaging lack to offer valuable information, such as Graves’ ophthalmopathy. It may also offer advantages for the study of systemic diseases, such as sarcoidosis or rheumatoid arthritis; for the staging of the disease; and for the study of associated pathologies.
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Somatostatin Analogues: From Research to Clinical Practice, First Edition. Edited by Alicja Hubalewska-Dydejczyk, Alberto Signore, Marion de Jong, Rudi A. Dierckx, John Buscombe, and Christophe Van de Wiele.
© 2015 John Wiley & Sons, Inc. Published 2015 by John Wiley & Sons, Inc.
Somatostatin is a cyclic peptide, which is present in the mammalian circulation in two bioactive forms: somatostatin-14 and somatostatin-28 [1, 2]. Somatostatin-14 was detected accidentally during studies of the distribution of growth hormone-releasing factor in the hypothalamus of rats [3, 4]. Subsequent studies showed that somato-statin is present and plays an inhibitory role in the regulation of several organ systems and tissues in man and other mammals, like the intestinal tract, the exocrine and endocrine pancreas, the central nervous system, the hypothalamus and the pituitary gland, the immune system, the retina, and the blood vessels. Somatostatin inhibits a
Somatostatin is a cyclic peptide, which is present in the mammalian circulation in two bioactive forms: somatostatin-14 and somatostatin-28 [1, 2]. Somatostatin-14 was detected accidentally during studies of the distribution of growth hormone-releasing factor in the hypothalamus of rats [3, 4]. Subsequent studies showed that somato-statin is present and plays an inhibitory role in the regulation of several organ systems and tissues in man and other mammals, like the intestinal tract, the exocrine and endocrine pancreas, the central nervous system, the hypothalamus and the pituitary gland, the immune system, the retina, and the blood vessels. Somatostatin inhibits a