Molecular mechanisms of pain in crystal-induced arthritis

Best Practice & Research Clinical Rheumatology 29 (2015) 98e110

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Molecular mechanisms of pain in crystal-induced arthritis R. Ramonda*, F. Oliviero 1, P. Galozzi 1, P. Frallonardo 1, M. Lorenzin 1, A. Ortolan 1, A. Scanu 1, L. Punzi 1 Rheumatology Unit, Department of Medicine e DIMED, University of Padova, via Giustiniani 2, 35128 Padova, Italy

a b s t r a c t Keywords: Crystal-induced arthritis Pain Monosodium urate crystals Pyrophosphate crystals Basic calcium phosphate crystals Prostaglandins Kinin system Interleukin-1b Colchicine NSAIDs

Crystal-induced arthritis (CIA) is characterized by an intense inflammatory reaction triggered by the deposition of monosodium urate, calcium pyrophosphate, and basic calcium phosphate crystals in articular and periarticular tissues. Severe, acute pain constitutes the most important clinical symptom in patients affected by these diseases. Pain along with redness, warmness, swelling, and stiffness in the affected joint arises abruptly in gout and disappears when the acute phase of the attack resolves. While an acute joint attack caused by calcium pyrophosphate crystals can mimic a gout flare, basic calcium phosphate crystal arthritis gives rise to a series of clinical manifestations, the most severe of which are calcific periarthritis, mostly asymptomatic, and a highly destructive arthritis known as Milwaukee shoulder syndrome, which is characterized by painful articular attacks. Pain development in CIA is mediated by several inflammatory substances that are formed after cell injury by crystals. The most important of these molecules, which exert their effects through different receptor subtypes present in both peripheral sensory neurons and the spinal cord, are prostaglandins, bradykinin, cytokines (in particular, interleukin (IL)-1b), and substance P. The pharmacological treatment of pain in CIA is strictly associated with the treatment of acute phases and flares of the disease, during

* Corresponding author. Tel.: þ39 049 8212190; fax: þ39 049 8212191. E-mail addresses: [email protected] (R. Ramonda), [email protected] (F. Oliviero), [email protected] (P. Galozzi), [email protected] (P. Frallonardo), [email protected] (M. Lorenzin), [email protected] (A. Ortolan), [email protected] (A. Scanu), [email protected] (L. Punzi). 1 Tel.: þ39 049 8212190. http://dx.doi.org/10.1016/j.berh.2015.04.025 1521-6942/© 2015 Elsevier Ltd. All rights reserved.

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which crystals trigger the inflammatory response. According to international guidelines, colchicines, nonsteroidal antiinflammatory drugs, and/or corticosteroids are first-line agents for the systemic treatment of acute CIA, while biologics, namely anti-IL-1b agents, should be used only in particularly refractory cases. © 2015 Elsevier Ltd. All rights reserved.

Introduction A common cause of pain and physical disability in adults, crystal-induced arthritis (CIA) is characterized by an intense inflammatory reaction that is triggered by the deposition of monosodium urate (MSU), calcium pyrophosphate (CPP), and basic calcium phosphate (BCP) crystals in articular and periarticular tissues [1,2]. While gout, which is caused by MSU crystals, constitutes the most common form of arthritis in males over the age of 40 with a prevalence of about 1e2% among adult men in Western countries [3], acute CPP crystal arthritis is the most common acute arthritis in older adults [4e6]. BCP crystals are a common cause of periarticular disease, which particularly affects the shoulder and which is characterized by calcifications that can lead to acute crystal-induced tendinitis or bursitis. Acute calcific tendinitis usually affects young or middle-aged adults [2]. The presence of articular BCP crystals has been reported to correlate strongly with the severity of articular damage in osteoarthritis [7]. The diagnosis of CIA is essentially based on the identification of MSU and CPP crystals in synovial fluid collected from the affected joints, while the presence of BCP crystals can be revealed using aspecific staining methods or sophisticated techniques such as electron microscopy and X-ray diffraction, which are not routinely available [8]. Clinical aspects Joint pain in CIA can be considered the consequence of the inflammatory process triggered by crystal deposition in the synovial tissues. This inflammatory reaction tends to be severe, and it is often accompanied by excruciating pain. Gout is characterized by two clinical phases, an acute and a chronic phase. The first features intermittent acute attacks that spontaneously resolve, typically over a period of 7e10 days, with asymptomatic periods between attacks. Onset is generally abrupt, and the affected joint is red, warm, swollen, and very tender. Some patients may experience a single episode, but often there are other attacks within 6 months to 2 years [9]. The second phase is notable for inadequately treated hyperuricemia with a transition to chronic tophaceous gout, which is often characterized by polyarticular attacks, symptoms between attacks, and crystal deposition (tophi) in soft tissues or joints. If it is not treated appropriately, attacks can involve other joints, occur more often, last longer, and lead to the transition to the chronic phase. The severity of gout is defined by the number of acute attacks and flares over the previous year. Acute CPP crystal arthritis is characterized by acute onset of pain, stiffness, swelling, and tenderness; the skin over the joint is red and inflamed. For the most part, it affects large joints such as knees, wrists, shoulders, and hips. CPP crystals can also deposit in the small joints of the hand and, unlike gout, rarely in the big toe. Uncommon locations of acute CPP crystal arthritis are the acromioclavicular and temporomandibular joints [10]. The deposition of BCP crystals can give rise to numerous clinical manifestations, the most severe of which are calcific periarthritis and the destructive arthropathy of the elderly known as Milwaukee shoulder syndrome [2]. While calcific periarthritis is mostly asymptomatic, Milwaukee shoulder syndrome is characterized by painful articular attacks.

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Uncommon pain manifestations in CIA, which are often missed or misinterpreted, can involve the spine. An acute vertebral pain accompanied by neurological signs, paresthesia, and at times paraplegia could be an expression of MSU, CPP, or BCP crystal deposition accompanied by a compression of the spinal cord and/or of nerve roots [11]. Spinal pain, in crystal deposition, has been found to mimic such diverse conditions as metastatic cancer [12], epidural abscess [13], and nerve compression syndromes [14]. Recent advances in knowledge concerning the genetics and pathophysiology mechanism of CIA have led to promising approaches to prevent and treat this painful disease. Pathophysiology of pain in CIA Pain can generally be divided into three types depending on its etiology and clinical features: nociceptive, pathological, and inflammatory [15]. Nociceptive pain is a protective response to potentially tissue-damaging noxious stimuli, such as temperature, chemical irritants, and mechanical forces. It is, therefore, pain that is essential to maintain bodily integrity [16]. Pathological pain is a disease state of the nervous system that can occur after damage to the nervous system (neuropathic pain) or as a result of altered neural processing (dysfunctional). Damaged nerve cells can generate pathologic ectopic discharges from the site of injury, which subsequently affect the surrounding healthy nerve fibers spontaneously generating pain [17]. Inflammatory pain, which occurs in response to tissue injury or infection, has a protective role of signaling the activation of the immune system. The inflammatory mediators that are released modulate nociceptors to perceive pain in an exaggerated and prolonged manner, thus heightening sensitivity and promoting recovering [18]. In particular, high levels of interleukin (IL)-1b hypersensitize nociceptors and play an important role in inflammatory pain and hyperalgesia, which eventually lead to neuropathic pain. The hypersecretion of IL-1b, as a product of Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation, is a well-known hallmark of gout and CPP crystal arthritis [19]. NLRP3 inflammasome has a central role in the inflammatory response to different danger-sensing molecules, such as MSU or CPP crystals, activating the IL-1b precursor. NLRP3 inflammasome also plays a pivotal role in a group of autoinflammatory diseases (AIDs), termed IL-1b inflammasomopathies, that include both hereditary periodic fevers, such as familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), pyogenic arthritis, and pyoderma gangrenosum and acne (PAPA), and complex disorders, such as type 2 diabetes mellitus and gout or CPP crystal arthritis [20,21]. This heterogeneous class of diseases are predominantly characterized by a dysregulation of the innate immune system in the absence of hightiter autoantibodies and antigen-specific T cells [22]. Several AIDs have a strong pain component that is linked to acute episodic flares and augmented levels of inflammatory mediators that affect the neuronal perception of pain. Neuronal-inflammation cross talk may be disrupted in AIDs and contribute to symptoms. The link between autoinflammation and pain has been further elucidated in animal models. A recent study identified a murine model for inflammatory pain from a mouse line with N-ethyl-N-nitrosurea mutagenesis [23]. These pstpip2 mutant mice with AIDs had an autoinflammatory phenotype associated with abnormal nociceptors responses. In accordance with other AIDs, CIA patients also present acute pain that can progress to a chronic state. Hypersecretion of inflammatory mediators, in particular IL-1b, and the consequent cellular infiltrate rich in neutrophils are typical features of gout and CPP crystal arthritis, presenting hyperalgesic properties [21]. IL-1b may, therefore, not only increase the pain that is perceived in gout but even amplify it. Nevertheless, the underlying pain mechanisms in CIA are still poorly understood. Pain experienced by CIA patients is usually associated with inflammatory conditions caused by crystal deposition in articular and periarticular tissues. It has thus been suggested that crystals do not directly induce nociception, but that they initiate the process by activating specific receptors via cytokines and other pro-nociceptive mediators released after crystal-induced activation of different cells. Indeed, according to several studies, pain is associated with a significantly increased crystal-induced leukocyte infiltration and activation [24]. More recently, it has been demonstrated that even resident cells, such as mast cells, may contribute to pain generation during

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acute attacks. In fact, Hoffmeister et al. demonstrated that mast cell membrane stabilization and prior degranulation of mast cells prevented nociceptive and edematogenic responses caused by MSU crystals [25]. Pain receptors Pain in CIA patients is characterized by a warm or hot feeling in the affected joints, a symptom implying the involvement of thermoreceptors expressed in sensory neurons. The involvement of some members of transient receptor potential (TRP) family ion channels in the crystal-induced nociceptive response has been identified. TRP channels are widely expressed in a large number of different tissues and cell types, and they are involved in various types of sensory reception, such as thermoreception, chemoreception, mechanoreception, and photoreception. Activated TRP channels cause ion flux that can lead to cell membrane depolarization. This, in turn, generates an action potential that results in a nerve impulse and a physiological sensation or perception. In vivo experiments have suggested that TRP vanilloid 1 (TRPV1), the capsaicin receptor, may be involved in crystal-induced pain through the release of mediators and the increased temperature of the crystal-injected tissue that stimulates this receptor. Indeed, a significant reduction in MSU-induced nociception and in edema has been observed in the paw of rats after they had received an injection of selective TRPV1 receptor antagonists and perineural capsaicin desensitization treatment [25]. TRP involvement was confirmed by an increase in the immunoreactivity of the TRPV1 channel in rat articular tissue after MSU crystal injection [26]. More recently, another TRP receptor, the TRP ankyrin 1 (TRPA1), has been shown to contribute to nociception and inflammation in CIA. TRPA1 seems to act as a sensor of oxidative stress, and its activation and sensitization by reactive oxygen species have been reported in several studies [27]. Using a rodent model of acute gout, Trevisan et al. demonstrated that an MSU-induced nociceptive response was reduced by TRPA1 antagonism, and that TRPA1 in sensory neurons was indirectly activated by crystals via H2O2 production [28]. The TRPA1 involvement has been confirmed by weight-bearing tests in wild-type (WT) and TRPA1 knockout mice. Injection of MSU crystals in hind knee joints did not induce any weight distribution change in TRPA1-deficient mice, while WT mice developed a reduction in spontaneous weight bearing on the affected limb [29]. It has been observed that TRPA1 and TRPV1 contributes synergically to the development of painful inflammatory responses evoked by crystals and that MSU increases the expression of both receptors [28]. TRPV1 and TRPA1 receptors are usually coexpressed in small-diameter C-fibers and mediumdiameter Ad fibers [30]. However, an increased sensitivity in C-fibers, but not in the Ad fibers, was observed in the ankle joint of chickens injected with sodium urate when compared with normal and adjuvant monoarthritic animals [31]. Pain mediators As stated above, nociceptive effects are mediated by several inflammatory substances produced after the interaction of pathogenic crystals with all of the major synovial cell types, including neutrophils, fibroblasts, and monocytes/macrophages [21]. The most important of these molecules also involved in joint pain are prostaglandin E2 (PGE2), bradykinin, cytokines (in particular, IL-1b), and substance P (Figs. 1 and 2). Prostaglandins PGE2 is considered to be the major contributor to inflammatory pain in arthritic conditions. Its production derives from the hydrolysis of arachidonic acid by, sequentially, cyclooxygenases (COX) and cytosolic and microsomal PGE synthases at the site of inflammation. Of the two COX isoforms, COX-2 is not at all or only slightly expressed under basal conditions in many tissues, but it is upregulated in response to proinflammatory factors. Pathogenic crystals are able to induce a rapid

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Fig. 1. Simplified scheme of the mechanisms involved in the development of pain in crystal-induced arthritis.

enhancement of COX-2 gene expression in tissues and in human monocytes through tyrosine phosphorylation, leading to the transcription of PGE2, which, in addition to their pain-triggering role, may participate in other symptoms of gouty arthritic flares, such as early vasodilation, edema, and leukocyte migration [32]. Fewer findings are available concerning the effect of crystals on microsomal PGE synthase-1, which is generally upregulated coordinately with COX-2, in response to pro-inflammatory stimuli [33]. The expression of both COX-2 and microsomal PGE synthase-1 at the messenger RNA (mRNA) and protein level is enhanced by IL-1b, in particular in the presence of bradykinin [34]. PGE2 exerts its effects through different E prostanoid (EP) receptor subtypes (EP1, EP2, EP3, and EP4) on plasma membranes (Fig. 2), coupled to different signal transduction pathways. EP1 and EP4 are present in both peripheral sensory neurons and the spinal cord [35]. EP1 and EP4 stimulation leads to the activation of protein kinase C (PKC) and PKA, respectively, in the peripheral nociceptors [36]. PKC and PKA, in turn, activate multiple molecules including TRPV1 channels, purinergic P2X3 receptors, calcium channels, and then voltage-gated sodium channels resulting in inflammatory hyperalgesia.

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Fig. 2. Mediators involved in the development of pain in crystal-induced arthritis.

Although there are no data on the role of pathogenic crystals in the release of PGE2 within the spinal cord, spinal PGE2 release was found to be increased after peripheral injuries or noxious stimuli with a biphasic response [37]. In the periphery, prostanoids have been shown to sensitize peripheral nociceptors to the effects of mediators such as bradykinin or histamine [38,39]. Kinin system In addition to the classic and alternative complement pathway, MSU crystals have also been shown to activate the Hageman factor and the contact system of coagulation, leading to the production of kallikrein, bradykinin, plasmin, and other mediators [40]. Bradykinin is one of the most potent pain mediators associated with inflammatory conditions, and a multitude of its excitatory and sensitizing effects on peripheral nociceptors have been described. Its levels have been shown to be affected, at least in part, by prostanoids, as nonselective COX inhibitors reduce bradykinin at the site of inflammation [41]. The finding suggests that there are mutual interactions between products of the arachidonic acideCOX cascade and kinin system in pain mediation. The effects of bradykinin are mediated by B1 and B2 receptors (Fig. 2), whose expression is enhanced by extracellular pro-inflammatory cytokines such as IL-1b and tumor necrosis factor alpha (TNF-a). Through phospholipase C and A2 activation, these receptors may contribute to the

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development of pain and hyperalgesia not only in the periphery but also in the spinal cord, as well as in higher centers [42]. It has been hypothesized that at the beginning of the inflammatory process the effects of kinin are predominantly mediated by the constitutive B2 receptors. B1 receptors may, instead, play an important role in persistent inflammatory pain, which is reflected by the antinociceptive activity of B1 receptor antagonists [38]. However, some authors have demonstrated that B2 receptor plays a role in maintaining MSU crystal-induced leukocyte infiltration and membrane permeability, and they have identified the B2 receptor as a potential therapeutic target for managing gout-related inflammation [43]. A more recent study demonstrating that peripheral B1 receptor antagonism reduces pain and edema (hallmark responses of an acute gouty attack) induced by MSU in rodents indicated that the B1 pathway may play a role in the onset of MSU crystal-induced inflammation [44]. The same study also found that a kinin B1 receptor antagonist reduced increased articular IL-1b levels and the massive leukocyte influx induced by MSU.

Cytokines A variety of inflammatory cytokines are released in joints in response to crystal deposition, and there is clear evidence of their involvement in inducing and maintaining the pain associated with CIA. Several studies have demonstrated that cytokines may modulate neuronal activity through a direct interaction with nociceptors in sensory neurons or indirectly by causing the release and/or activation of other effectors, such as other cytokines, prostanoids, kinins, and members of the complement pathways. Particular attention has recently been focused on the role of IL-1b in crystal-induced inflammation and pain. IL-1b is synthesized as a precursor protein (pro-IL-1b), which is cleaved into the active form by the enzyme caspase-1, via NALP3 inflammasome activation. IL-1b may contribute to the development of pain through upregulation, at both the transcriptional and posttranscriptional levels, of other pro-nociceptive mediators, including nerve growth factor, PG, IL-6, and substance P (Fig. 2) [45-48]. However, IL-1b action can also occur directly on nociceptors. Indeed, IL-1 receptor type I (IL-1R1) expression has been observed in sensory neurons [49], and it is known that IL-1b modulates neuronal excitability by affecting neuronal receptors, including TRPV1, sodium channels, gamma-aminobutyric acid (GABA), and N-methyl-D-aspartate (NMDA) receptors [49-52]. It has also been demonstrated that IL-1b is able to increase the expression of neuronal receptors, such as TRPA-1 [53]. Blockade of IL-1 in a mouse model of acute gouty ankle arthritis using IL1R1 knockouts or mIL1 Trap (a murine IL-1b-blocking agent) led to the prevention and suppression of MSU crystal-induced hyperalgesia and inflammation [54]. Another cytokine that plays an important role in regulating inflammatory immune responses induced by microcrystals is transforming growth factor beta 1 (TGFb1), which is an important antiinflammatory mediator involved in inducing auto-remission of inflammation in acute gout attacks [55]. TGFb1 also prevents nitric oxide production in macrophages [56] that is strongly implicated in the development of neuropathic pain [57]. Although no studies have been conducted as yet, it can be hypothesized that TGFb1 or agents that induce its activity could be an effective therapy for crystalinduced pain.

Substance P When C-fiber sensory nerves are stimulated, a number of different neuropeptides, such as substance P, are released. Substance P, a small peptide with many pro-inflammatory effects, is involved in the neurotransmission of pain and noxious stimuli from peripheral receptors to the central nervous system. Studies focusing on immunohistochemical localization of substance P have shown a reduction in the labeled nerve fibers following injection of sodium urate into the ankle joint of chicks. This

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demonstrates that a neurogenic depletion of substance P from peripheral nerve fibers in the synovial and subsynovial tissue is produced during painful gout [58]. The biological effects of substance P are mediated by its binding to the neurokinin-1 (NK1) receptor (Fig. 2). Injection of NK1 receptor antagonists into the paws of rats significantly prevented MSUinduced nociception and edema [25]. From pain mechanisms to therapeutic strategies Treatment for CIA-related pain is generally prescribed for the acute phase of the disease, during which crystals trigger an inflammatory response. In accordance with international standards, the following factors must be considered for evaluation when therapy for pain is being decided: the presence of contraindications, the patient's previous experience with various treatments, the time after flare onset that treatment will be initiated, and the number and type of joints involved. Colchicine A widely used and recommended first-line therapy for the treatment of acute gouty arthritis flares is colchicine, an alkaloid originally extracted from Colchicum plant known to the Romans [59]. Currently administrated orally to minimize systemic reactions associated with the intravenous form, colchicine is effective at low dosages in acute flares as well as in long-term prophylactic maintenance therapy, as outlined in EULAR (European League Against Rheumatism) and ACR (American College of Rheumatology) recommendations [60,61]. The EULAR guidelines recommend 1 mg of colchicine within 12 h of flare onset followed by 0.5 mg 1 h later. A dosage of 0.5e1 mg is, instead, recommended for prophylactic treatment [62]. As opposed to gout, it is less evident in CPP-related arthritis if low doses of colchicine or nonsteroidal anti-inflammatory drugs (NSAIDs) are as effective as prophylactic treatment. As it is a substrate of p-glycoprotein transporter and cytochrome P450 3A4, colchicine is contraindicated in patients with renal or hepatic impairment receiving both enzyme inhibitors [63]. Although colchicine may be preferred in some situations due to the possibility of dose titration, in clinical practice NSAIDs and corticosteroids are considered the treatment of choice. The exact mechanism by which colchicine relieves pain is not completely understood. It is widely known that colchicine binds to both a- and b-tubulin to create a complex that prevents the formation of microtubules [64]. As a consequence, processes that require microtubules to generate inflammatory mediators, such as recruitment of cytosolic component (mitochondria) or proteins (kinases), are susceptible to colchicine treatment. Moreover, colchicine has been found to downregulate multiple pro-inflammatory pathways through inhibition of NLRP3 inflammasome, suppressing nuclear factor kappa B (NF-kB) and TNF-a receptor expression and blocking IL-1b secretion [65,66]. Colchicine also interferes with neutrophil adhesion and recruitment to the site of inflammation by decreasing L-selectin expression and altering the distribution of E-selectin on endothelial cells [67]. NSAIDs NSAIDs are widely used in the symptomatic management of many rheumatic diseases characterized by chronic musculoskeletal pain and diverse forms of acute pain [68]. These drugs block PG production by inhibiting COX activity with consequent analgesic effects. As outlined by the EULAR evidence-based recommendations for gout and CPP deposition management [60,69], NSAIDs, together with colchicine, are first-line options for the systemic treatment of acute CIA. Although COX-2 inhibitors are likely to be associated with significantly fewer total and gastrointestinal adverse events, a recent systematic review indicated that selective COX-2 inhibitors and nonselective NSAIDs are equally beneficial in terms of pain relief in acute gout [70].

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Most traditional NSAIDs inhibit COX-1 also in the platelets and in the gastroduodenal mucosa, and in so doing they promote bleeding and gastrointestinal ulceration. COX-2 selective and traditional NSAIDs have been associated with cardiovascular (CV) risks. In CIA, nevertheless, the CV risk linked to NSAIDs should be considered lower with respect to that associated with other chronic diseases as the use of these drugs is mostly limited to the phase of the acute attack and/or during prophylaxis. In this latter case, NSAIDs are recommended at low dosage during the first 6 months of urate-lowering drug therapy in patients intolerant or refractory to colchicine. In any case, traditional NSAIDs must always be used with caution in patients with renal disease or high CV risk in view of pharmacological interactions with other drugs such as low-dose aspirin and anticoagulants. Achieving optimal levels of serum uric acid in these patients leads to the reduction in NSAID consumption for disease flares. Steroids Corticosteroids are widely used in the treatment of joint pain or inflammation in different arthritic conditions. Aside from their effects on lipocortins, which suppress the release of arachidonic acid, corticosteroids inhibit inflammatory and immune responses by downregulating the expression of proinflammatory transcription factors such as AP-1 and NF-kB and reducing pro-inflammatory gene expression via activation of the glucocorticoid receptor [71]. In acute CIA, glucocorticoids have been shown to prevent activation of NF-kB by TNF-a or IL-1b and to increase the expression of IkB, which, in the cytoplasm, prevents translocation of NF-kB to the nucleus [72]. According to the international guidelines including the most recent recommendations proposed by EULAR [60], corticosteroids are an effective and safe alternative in the event of intolerance or contraindications to NSAIDs in CIA. In gout, the mean dose suggested by these recommendations is 30e35 mg/day of equivalent prednisone for 3e5 days; lower doses are suggested in CCP and BCP crystal arthritis. Intra-articular corticosteroid therapy can be considered a good option for patients with high CV risk, at least during the acute attack. A short tapering course of oral glucocorticoids, parenteral glucocorticoids, or adrenocorticotropic hormone (ACTH) may be effective in acute CPP crystal arthritis that is not amenable to intra-articular glucocorticoid injection, and these are alternatives to colchicine and/or NSAID [69]. In the event of failure of these treatments (colchicine, NSAIDs and steroids), methotrexate can also be used in CPP crystal arthritis [73]. Biologics Comorbidities, resistance to standard therapy, or side effects could limit the use of NSAIDs, colchicines, or steroids, in which case alternative therapies are necessary. Recently, IL-1 inhibition has proved to be an efficacious method to manage pain and inflammation in CIA. Blockade of IL-1 activity by means of the IL-1 receptor antagonist (IL-1Ra, anakinra) in patients with acute gout led to a 79% diminution of pain by day 3 after the first injection [74]. More recently, a study focusing on 40 patients with gout receiving anakinra demonstrated that 36 had a good response to therapy and the mean pain score on a 100-mm visual analog scale (VAS) fell from 73.5 to 25.0 [75]. In another study focusing on 26 patients with gout, pain improved significantly within 24 h of treatment in 67% of the patients, and 72.5% of the patients achieved complete symptom resolution within 5 days [76]. In agreement with this result, a rapid, marked reduction in joint pain was observed in patients with CPP crystal-induced inflammatory arthritis following treatment with anakinra [77,78]. Two other IL-1 inhibitors, rilonacept and canakinumab, were demonstrated to be efficacious in reducing pain and signs of inflammation in gout. The former, a soluble receptor-Fc fusion protein (IL-1 Trap), was linked to a 50% VAS overall pain reduction after 2 weeks of treatment and a 75% reduction after 6 weeks in patients with chronic refractory gout [79]. Studies comparing canakinumab, an anti-IL1b monoclonal antibody, with triamcinolone acetonide demonstrated that the former can improve pain and swelling more than the latter in patients with acute gout [80,81].

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IL-1 inhibitors are generally well tolerated, and they may offer therapeutic benefit in reducing pain and flare frequency in patients with gout. In view of the risk of infection associated with prolonged administration and their high cost, IL-1 blockers can be used only in cases refractory or intolerant to traditional therapy. Preventing chronic evolution Urate-lowering therapy (ULT) reduces tissue urate levels below the saturation point for crystal formation and maintains them at a low level that promotes crystal dissolution. ULT can thus prevent acute flares and the development of the chronic form. According to recent EULAR recommendations, the levels of serum acid uric should be < 6 mg/dl (360 mmol/l) [60]. The two groups of drugs currently used to reduce the serum urate level are inhibitors of xanthine oxidase, enzymes involved in the synthesis of uric acid from xanthine and hypoxanthine, and uricosuric drugs, which increase uric acid excretion. With regard to the former, the most frequently used is allopurinol; febuxostat is instead prescribed in patients intolerant or refractory to allopurinol [60]. Uricosuric drugs including sulphinpyrazone, probenecid, and benzbromarone may be indicated in certain groups of patients, whereas a new class of recombinant uricases (pegloticase) administered by intravenous infusion may achieve rapid urate-lowering effects (not available in Italy) [82]. Preventing the development of the chronic form of CPP crystal arthritis remains a major challenge as, unlike gout, there is no definitive treatment to prevent formation or enhance dissolution of CPP crystals in affected joints or tissues. As magnesium has been shown to solubilize CPP crystals in vitro, one small double-blind, placebo-controlled clinical study was undertaken in patients with symptomatic knee osteoarthritis plus CPP crystal arthritis to assess the effect of magnesium administration on disease evolution. Despite effective pain diminution, the study did not show any reduction in terms of radiographic calcifications in the patients receiving magnesium compared to those receiving placebo [83]. Another theoretical pharmacological approach could be the use of drugs formulated to modulate pyrophosphate levels, thus influencing CPP crystal formation and dissolution. To date, no clinical studies have been carried out to verify in vitro findings [84]. Summary Pain, which occurs in response to inflammatory processes, is the most important feature of CIA. There is an abundant release of inflammatory molecules, including PGE2 and kinins, directly involved in the development of pain by both the direct and indirect stimulation of nociceptors in the course of crystal-induced inflammatory processes. IL-1b, which represents the most important cytokine released during crystal-induced inflammatory processes, is also implicated in pain at both the peripheral and central levels. In fact, although little is known about the role of IL-1b in CIA pain, it is conceivable that it contributes to nociceptive responses through indirect mechanisms, such as the release and the activation of other nociceptive molecules including PGE2 and substance P. Clinically, pain associated with CIA leads to functional impairment and disability in a large portion of patients. Early diagnosis and prompt therapeutic intervention, always taking into consideration the patient's characteristics and comorbidities, are thus essential. In this context, colchicine and/or NSAIDs are considered first-line agents for the systemic treatment of acute CIA. Corticosteroids are an effective and safe alternative in the event of contraindications or intolerance, and, by intra-articular administration, also for patients with high CV risk. Although biologics have been introduced for CIA management, in view of their high cost, they can be considered a treatment option only in refractory cases. Conflicts of interest None to declare.

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Practice points  Causing pain and physical disability, crystal-induced arthritis affects a large part of the population.  Pain is due to inflammatory reactions triggered by pathogenic crystals such as monosodium urate, calcium pyrophosphate, and basic calcium phosphate crystals.  Deposited in articular and periarticular tissues, these crystals invoke a strong release of inflammatory molecules, some of which are linked to pain development.  The most important pain mediators, prostaglandins E2, bradykinin, interleuchin-1b, and substance P, lead to peripheral and central sensitization.  Pharmacological treatment aims to reduce acute attacks. According to international guidelines, colchicine, NSAIDs, and/or corticosteroids are first-line agents, while IL-1b blockers should be used in unresponsive and/or refractory cases.

Acknowledgment The authors would like to express their appreciation to Linda Inverso for her help in preparing the English version this manuscript.

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