blind, active Comparator-controlled study designed to compare the efficacy and safety of adalimumab plus MTX versus MTX monotherapy or adalimumab monotherapy in patients with early, aggressive RA who had not previously received MTX treatment (PREMIER study), the overall rate of infectious adverse events (AEs) did not differ significantly among the 3 treatment groups (123, 110, and 119 events per 100 patient-years in the combination therapy, adalimumab monotherapy, and MTX monotherapy groups, respectively) (Breedveld, Weisman et al. 2006). The rate of serious infections in the adalimumab monotherapy group was significantly lower than that in the combination treatment group, but not significantly different compared with the MTX monotherapy group. Notably, serious infections were more common in the combination therapy arm with 9 serious infections reported, including 3 pulmonary infections (1 case of pleural TB) and 1 case each of sinus infection, wound infection, septic arthritis, infected hygroma, cellulitis, and urinary tract infection. In the adalimumab monotherapy arm, serious infections included 1 case each of pneumonia, cellulitis, and septic arthritis. In the MTX monotherapy arm, the 7 serious infections consisted of 2 cases of pneumonia and 1 each of septic arthritis, sinusitis, abscess, bacteremia, and parotitis. The long term safety of adalimumab was investigated in the 4 year open-label extension of the ARMADA trial (Weinblatt, Keystone et al. 2006). The rate of serious infections was slightly lower throughout the entire study than in the blinded period alone with the most common serious infections reported being pneumonia, urinary tract infections and septic arthritis. A PPD skin test was performed at the screening visit for all patients. Standard chest radiographs were also taken at the screening visit and at week 24. Notably, at baseline, 11/271 (4.1%) randomized patients had positive PPD results at screening, including 9/209 (4.3%) adalimumab treated patients and 2/62 (3.2%) placebo treated patients. These patients were treated with TB prophylaxis in accordance with routine medical practice. No cases of TB or other opportunistic infections were reported. The safety profile of adalimumab was analyzed further in a cumulative analysis of data from 10050 patients who participated in randomized controlled trials, open label extensions, and two phase IIIb open label trials, representing 12506 patient-years (PYs) of adalimumab exposure (Schiff, Burmester et al 2006). The rate of serious infections in the clinical trial safety database as of April 2005 was 5.1/100 PYs. This rate is nearly identical to that observed in August 2002 (4.9/100 PYs) and was similar to rates reported for the general RA population. Four cases of histoplasmosis were reported, all in endemic areas (0.03/100 PYs). No cases of

coccidioidomycosis have been reported in RA clinical trials.

**2.2.2 Registry data, observational data and chart reviews**

infections in certain population groups (Furst 2010).

The safety profile of anti-TNF agents in the everyday clinical practice was elucidated further by registry data analysis, observational studies and chart reviews. Data derived from these studies could be highly informative; however the lack of a standard comparator, strict inclusion and exclusion criteria and the inherent differences in patient characteristics with respect to ethnic, geographical and socio-economical characteristics often reduce their credibility and, produce desperate results and do not allow direct comparisons among different studies. Nevertheless, these studies become important when they investigate specific or relatively rare types of infections and raise specific concerns with regards to Numerous case reports have raised awareness to rare bacterial infections in RA patients treated with anti-TNF. These included reports on reactivation of brucellosis (Jimenez, Colmenero et al. 2005), *Capnocytophaga cynodegmi*-related cellulitis (Gerster and Dudler 2004), *Roseomonas mucosa* induced septic arthritis (Sipsas, Papaparaskevas et al. 2006), and *Propionebacterim acnes*-related endogenous endophthalmitis (Montero, Ruiz-Moreno et al. 2006).

#### **2.2.4 Meta-analyses**

One solution to the lack of precision in the estimates of harm derived from individual randomized trials is to pool their results using meta-analysis. Results however from the two

Infectious Complications of Anti-Tumour Necrosis Factor-α Therapy in Rheumatoid Arthritis 99

infliximab package insert), differences in proportions of international patients treated with the 2 agents, or other factors (Gardam, Keystone et al. 2003; Mohan, Cote et al. 2004). Overall, in a large systematic review of infectious complications of TNF antagonists extracted from 35275 distinct reports from the AERS database between for January 1998– September 2002, granulomatous infections were reported at rates of ∼239 per 100000 patients who received infliximab and ∼74 per 100,000 patients who received etanercept (P <0.001) (Wallis, Broder et al. 2004). TB was the most frequently reported disease, occurring in ∼144 and ∼35 per 100,000 infliximab-treated and etanercept-treated patients, respectively P<0.001. Candidiasis, coccidioidomycosis, histoplasmosis, listeriosis, nocardiosis, and infections due to nontuberculous mycobacteria were reported with significantly greater frequency among infliximab-treated patients. 72% of these infection occurred 90 days after starting infliximab treatment, and 28% occurred after starting etanercept treatment P<0.001. These data indicated a relative risk of granulomatous infection that was >3 among patients who received infliximab compared to those who received etanercept. The clustering of reports shortly after initiation of treatment with infliximab was consistent with reactivation

Geographical associations between anti-TNF therapy and specific granulomatous diseases have been suggested. For example, disseminated histoplasmosis has been reported more frequently in endemic regions in the US (Lee, Slifman et al. 2002). In a review of the FDA passive surveillance database, nine cases of invasive disseminated histoplasmosis associated with infliximab and 1 associated with etanercept were reported. In patients treated with infliximab, manifestations of histoplasmosis occurred within 1 week to 6 months after the first dose and typically included fever, malaise, cough, dyspnea, and interstitial pneumonitis. All patients had received concomitant immunosuppressive medications in addition to infliximab or etanercept, and all resided in histoplasmosis endemic regions of central US (Lee, Slifman et al. 2002). Similarly, anti-TNF therapy was shown to be associated with increased reports of

A major factor that has influenced data relating to the risk of TB associated with biological treatments has been the introduction of vigorous screening of patients participating in clinical trials; hence rates for newer biological agents such as abatarcept may be biased. Screening for TB exposure with PPD skin testing or newer interferon-based serum tests (although their optimal use in this setting is not yet clear) should be performed before beginning therapy with anti-TNF agents (Winthrop and Chiller 2009). Anergy is known to occur in patients with RA or Crohn's disease, and the possibility of false-negative skin tests should be taken into consideration. Nevertheless from a therapeutic point of view, since the implementation of strict guidelines (e.g. BTS recommendations, 2005) with regards to screening patients for exposure risks and treating latent TB prior to initiation of any biological treatment, the risk of tuberculosis has decreased. This is depicted in the data from the Spanish Registry showing that these strategies have resulted in dropping the rates of active TB in RA patients by 83% reaching those observed for RA patients not treated with

TNF is essential for granuloma formation and maintenance which are key components of host defences against intracellular pathogens (Furst, Wallis et al. 2006). TNF can support

leishmaniasis in endemic areas in Europe (Xynos, Tektonidou et al. 2009).

TNF antagonists (Carmona, Gomez-Reino et al. 2005).

**2.3.1 TNF-α pathophysiology and infections**

of latent infection.

existing meta-analyses studies on anti-TNF therapy and risk of infection are disparate. A meta-analysis of nine randomized, controlled studies including 3493 patients with RA who received anti-TNF antibody treatment (infliximab and adalimumab) and 1512 patients who received placebo reported a doubled risk of serious infection [odds ratio (OR) 2.0, 95% CI 1.3–3.1] and a tendency towards a dose–response association (Bongartz, Sutton et al. 2006). On the contrary, a second meta-analysis of five published, placebo-controlled trials involving a total of 2945 randomized patients, who received at least one dose of abatacept (0.5, 2 or 10 mg/kg) (n=1960) or placebo (n=985) for a duration of treatment ranging between 24 and 48 weeks did not reveal a statistically significant increased risk of serious infection for abatarcept (Salliot, Dougados et al. 2009). The 49 serious infections reported in the abatacept cohort were mainly broncho-pulmonary, streptococcal and pyogenic septicaemia, staphylococcal arthritis, abscesses, gastrointestinal infections (6 of whom 3 diverticulitis), dermatological infections (six of whom one was a cellulitis) and pyelonephritis. One case of unconfirmed TB and one case of pulmonary aspergillosis were reported. The last patient (who had a history with TB and pulmonary fibrosis) died with aspergillosis and *Pseudomonas aeruginosa* septicaemia.

#### **2.3 Tuberculosis and opportunistic infections**

As shown earlier, the incidence of TB in pre-registration clinical trials has been low. It was only after licensing of these medications that post-marketing surveillance registers showed results suggestive a strong association between ant-TNF treatment and TB. Keane *et al* analysed data from the US Food and Drug Administration's ( FDA) Adverse Event Reporting System (AERS) for reports of TB with infliximab from its licensure in 1998 through May 29, 2001 (Keane, Gershon et al. 2001). There were 70 reported cases of TB after treatment with infliximab for a median of 12 weeks. In 48 patients, TB developed after three or fewer infusions and 40 of the patients had extrapulmonary disease (17 had disseminated disease, 11 lymph-node disease, 4 peritoneal disease, 2 pleural disease, and 1 each meningeal, enteric, paravertebral, bone, genital, and bladder disease). An estimated rate of 24.4 cases of tuberculosis per 100 000 in the USA compared with a background rate in American patients with RA who had not received the drug of 6.2 cases per 100000 was calculated. The rather atypical presentation of the disease (e.g. extrapulmonary dissemination), the temporal relation between development of active tuberculosis and the start of therapy, the age of the patients (median, 57 years), the small number of cases with reported recent exposure to TB, and the low incidence of TB in the countries from which the reports were received suggested reactivation of the disease (Keane, Gershon et al. 2001).

As of March, 2002, 121000 patients had been treated with etanercept worldwide with about 94% of the use in the USA. In a search of the FDS's AERS database reported up to March 2002, Mohan and co-workers detected 25 cases of tuberculosis that occurred during or after etanercept therapy (Mohan, Cote et al. 2004). Patients with etanercept-associated TB were fewer but clinically similar to those with infliximab-associated TB (Keane, Gershon et al. 2001). The numbers of patients who had been exposed to etanercept and infliximab were roughly similar, yet the TB rate for US patients using etanercept was lower than that for patients using infliximab (∼10 vs. ∼41 cases/100000 patient-years of exposure). It has been proposed that this difference might be due to the divergent ways in which the 2 agents neutralize TNF-α, the use of MTX concurrently with infliximab (as indicated for RA in the

existing meta-analyses studies on anti-TNF therapy and risk of infection are disparate. A meta-analysis of nine randomized, controlled studies including 3493 patients with RA who received anti-TNF antibody treatment (infliximab and adalimumab) and 1512 patients who received placebo reported a doubled risk of serious infection [odds ratio (OR) 2.0, 95% CI 1.3–3.1] and a tendency towards a dose–response association (Bongartz, Sutton et al. 2006). On the contrary, a second meta-analysis of five published, placebo-controlled trials involving a total of 2945 randomized patients, who received at least one dose of abatacept (0.5, 2 or 10 mg/kg) (n=1960) or placebo (n=985) for a duration of treatment ranging between 24 and 48 weeks did not reveal a statistically significant increased risk of serious infection for abatarcept (Salliot, Dougados et al. 2009). The 49 serious infections reported in the abatacept cohort were mainly broncho-pulmonary, streptococcal and pyogenic septicaemia, staphylococcal arthritis, abscesses, gastrointestinal infections (6 of whom 3 diverticulitis), dermatological infections (six of whom one was a cellulitis) and pyelonephritis. One case of unconfirmed TB and one case of pulmonary aspergillosis were reported. The last patient (who had a history with TB and pulmonary fibrosis) died with

As shown earlier, the incidence of TB in pre-registration clinical trials has been low. It was only after licensing of these medications that post-marketing surveillance registers showed results suggestive a strong association between ant-TNF treatment and TB. Keane *et al* analysed data from the US Food and Drug Administration's ( FDA) Adverse Event Reporting System (AERS) for reports of TB with infliximab from its licensure in 1998 through May 29, 2001 (Keane, Gershon et al. 2001). There were 70 reported cases of TB after treatment with infliximab for a median of 12 weeks. In 48 patients, TB developed after three or fewer infusions and 40 of the patients had extrapulmonary disease (17 had disseminated disease, 11 lymph-node disease, 4 peritoneal disease, 2 pleural disease, and 1 each meningeal, enteric, paravertebral, bone, genital, and bladder disease). An estimated rate of 24.4 cases of tuberculosis per 100 000 in the USA compared with a background rate in American patients with RA who had not received the drug of 6.2 cases per 100000 was calculated. The rather atypical presentation of the disease (e.g. extrapulmonary dissemination), the temporal relation between development of active tuberculosis and the start of therapy, the age of the patients (median, 57 years), the small number of cases with reported recent exposure to TB, and the low incidence of TB in the countries from which the reports were received suggested reactivation of the disease (Keane, Gershon et al. 2001).

As of March, 2002, 121000 patients had been treated with etanercept worldwide with about 94% of the use in the USA. In a search of the FDS's AERS database reported up to March 2002, Mohan and co-workers detected 25 cases of tuberculosis that occurred during or after etanercept therapy (Mohan, Cote et al. 2004). Patients with etanercept-associated TB were fewer but clinically similar to those with infliximab-associated TB (Keane, Gershon et al. 2001). The numbers of patients who had been exposed to etanercept and infliximab were roughly similar, yet the TB rate for US patients using etanercept was lower than that for patients using infliximab (∼10 vs. ∼41 cases/100000 patient-years of exposure). It has been proposed that this difference might be due to the divergent ways in which the 2 agents neutralize TNF-α, the use of MTX concurrently with infliximab (as indicated for RA in the

aspergillosis and *Pseudomonas aeruginosa* septicaemia.

**2.3 Tuberculosis and opportunistic infections**

infliximab package insert), differences in proportions of international patients treated with the 2 agents, or other factors (Gardam, Keystone et al. 2003; Mohan, Cote et al. 2004). Overall, in a large systematic review of infectious complications of TNF antagonists extracted from 35275 distinct reports from the AERS database between for January 1998– September 2002, granulomatous infections were reported at rates of ∼239 per 100000 patients who received infliximab and ∼74 per 100,000 patients who received etanercept (P <0.001) (Wallis, Broder et al. 2004). TB was the most frequently reported disease, occurring in ∼144 and ∼35 per 100,000 infliximab-treated and etanercept-treated patients, respectively P<0.001. Candidiasis, coccidioidomycosis, histoplasmosis, listeriosis, nocardiosis, and infections due to nontuberculous mycobacteria were reported with significantly greater frequency among infliximab-treated patients. 72% of these infection occurred 90 days after starting infliximab treatment, and 28% occurred after starting etanercept treatment P<0.001. These data indicated a relative risk of granulomatous infection that was >3 among patients who received infliximab compared to those who received etanercept. The clustering of reports shortly after initiation of treatment with infliximab was consistent with reactivation of latent infection.

Geographical associations between anti-TNF therapy and specific granulomatous diseases have been suggested. For example, disseminated histoplasmosis has been reported more frequently in endemic regions in the US (Lee, Slifman et al. 2002). In a review of the FDA passive surveillance database, nine cases of invasive disseminated histoplasmosis associated with infliximab and 1 associated with etanercept were reported. In patients treated with infliximab, manifestations of histoplasmosis occurred within 1 week to 6 months after the first dose and typically included fever, malaise, cough, dyspnea, and interstitial pneumonitis. All patients had received concomitant immunosuppressive medications in addition to infliximab or etanercept, and all resided in histoplasmosis endemic regions of central US (Lee, Slifman et al. 2002). Similarly, anti-TNF therapy was shown to be associated with increased reports of leishmaniasis in endemic areas in Europe (Xynos, Tektonidou et al. 2009).

A major factor that has influenced data relating to the risk of TB associated with biological treatments has been the introduction of vigorous screening of patients participating in clinical trials; hence rates for newer biological agents such as abatarcept may be biased. Screening for TB exposure with PPD skin testing or newer interferon-based serum tests (although their optimal use in this setting is not yet clear) should be performed before beginning therapy with anti-TNF agents (Winthrop and Chiller 2009). Anergy is known to occur in patients with RA or Crohn's disease, and the possibility of false-negative skin tests should be taken into consideration. Nevertheless from a therapeutic point of view, since the implementation of strict guidelines (e.g. BTS recommendations, 2005) with regards to screening patients for exposure risks and treating latent TB prior to initiation of any biological treatment, the risk of tuberculosis has decreased. This is depicted in the data from the Spanish Registry showing that these strategies have resulted in dropping the rates of active TB in RA patients by 83% reaching those observed for RA patients not treated with TNF antagonists (Carmona, Gomez-Reino et al. 2005).

#### **2.3.1 TNF-α pathophysiology and infections**

TNF is essential for granuloma formation and maintenance which are key components of host defences against intracellular pathogens (Furst, Wallis et al. 2006). TNF can support

Infectious Complications of Anti-Tumour Necrosis Factor-α Therapy in Rheumatoid Arthritis 101

Anti-TNF therapy for RA in the setting of Hepatitis C (HCV) infection could be of particular interest in light of the existing evidence suggesting a role for inflammatory cytokines including TNF-α in the mediating hepatocyte destruction in chronic CMV (Parke and Reveille 2004). It may therefore carefully assumed that anti-TNF agents may be safer in patients infected with HCV rather than HBV (Shale, Seow et al. 2010) and furthermore this notion has been tested in a phase 2 randomised, double-blind, placebo-controlled study where etanercept given for 24 weeks as adjuvant therapy to interferon and ribavirin was shown to significantly improve virological response among patients with chronic HCV and was associated with decreased incidence of most adverse effects associated with interferon and ribavirin (Zein 2005). Although overall experience to date with anti-TNF agents in the chronic HCV setting suggests an acceptable short-term safety profile (Marotte, Fontanges et

The safety of anti-TNF therapy in HIV is a controversial subject. TNF inhibition in the setting of HIV induced immunosuppression does not appear appealing in view of the potential role for TNF-α in the host defence against infections. Notably, in an early report, the use of etanercept in HIV positive patient with psoriasis and CD4 count of <200/mm3 was associated with polymicrobial infections prompting termination of the treatment (Aboulafia, Bundow et al. 2000). Subsequent reports though have shown a favourable safety profile (Kaur, Chan et al. 2007; Cepeda, Williams et al. 2008), yet clinical decisions should be taken cautiously; careful consideration of the risks and benefits for the individual patient would be needed and close clinical and virological monitoring should always be warranted. The safety of TNF inhibitors in patients with herpes virus (HSV) infections has also been considered. In particular the risk of herpes zoster infection in patients with RA is twice as much even in the absence of therapy (Wolfe, Michaud et al. 2006; Smitten, Choi et al. 2007) and severe herpes zoster infections have been reported in randomised controlled trials and their open-label follow up studies in patients with RA receiving the TNF inhibitors infliximab or adalimumab (Lipsky, van der Heijde et al. 2000; Furst, Schiff et al. 2003; Keystone, Kavanaugh et al. 2004; Maini, Breedveld et al. 2004). A study by Strangfeld *et al* (Strangfeld, Listing et al. 2009) addressed the question whether this association actually represents a true association between TNF inhibitors reactivation of latent viral infections or simply reflects the increased risk of herpes zoster infection in RA patients (Bongartz and Orenstein 2009). In this prospective cohort the investigators identified 86 episodes of herpes zoster among 5040 patients from the German biologics register RABBIT, receiving anti-TNF agents or conventional DMARDs. Adjusted for age, RA severity and glucocorticoid use, a significant increased risk was observed for treatment with the monoclonal antibodies (HR, 1.82 [95% CI, 0.73-2.55]), although this risk was lower than the threshold (of 2.5) for clinical significance. No significant associations were found for etanercept use (HR 1.36, 95% CI 0.73-2.55) or for anti-TNF treatment (HR 1.63, 95% CI 0.97-2.74) as a class. Equally important, the incidence rate of multidermatomal and ophthalmic zoster was higher in patients taking TNF inhibitors implying severe disease often requiring hospitalisation (Bongartz and Orenstein 2009). Nevertheless, anti-TNF therapy can generally be restarted following temporary interruption and conventional anti-viral therapy until the skin lesions are completely healed (Wendling, Streit et al. 2008). Isolated varicella infections have also been reported in RA patients receiving anti-TNF therapy (Vonkeman, ten Napel et al. 2004; Choi, Kim et al. 2006; Lee, Kim et al. 2007). Notably the rash in one of these cases was

al. 2007), long-term issues remain to be clarified.

host immunity through the secretion of chemokines, up-regulation of adhesion molecules and the induction of macrophage apoptosis. While TNF blockers may therefore interfere with these important immune functions, other less predictable immune effects have been seen with these agents. In particular, TNF-blockers have been shown to diminish interferon (IFN)-γ effects and stimulate apoptosis of key immune cells, including monocytes, CD4+ T helper cells and Mtb-reactive CD8+ T cells. Anti-TNF therapy is also associated with increased regulatory T cell (Treg) function, which has been linked with susceptibility to TB (Harris and Keane 2010). TNF-α neutralization in mice has resulted in fatal reactivation of persistent tuberculosis characterized by a moderately increased tissue bacillary burden and severe pulmonic histopathological deterioration that was associated with changes indicative of squamous metaplasia and fluid accumulation in the alveolar space (Mohan, Scanga et al. 2001).

#### **2.4 Postoperative infections**

Although several studies have attempted to address the risk of postoperative infection, limited statistical precision has been a major concern. The largest study reported a 50% (but not statistically significant) increased risk of surgical site infections for those patients who continued therapy peri-operatively (den Broeder, Creemers et al. 2007). Nevertheless, considering the morbidity of orthopedic surgical site infections (especially prosthesis infections) as compared to a transient surge in disease activity, withholding anti-TNF agents peri-operatively appears to be the most reasonable and prudent approach at present (Bongartz 2007).

#### **2.5 Viral infections**

Reactivation of Hepatitis B (HBV) infection is a well described complication of immunosuppression in the setting of organ transplantation or cancer chemotherapy, occurring in up to 50% of patients where concomitant anti-viral treatment is not applied (Shale, Seow et al. 2010). The use of anti-TNF medications has been reported in isolated case reports, case series and chart reviews with a variety of outcomes ranging from apparent viral clearance to fatal hepatitis. In a comprehensive review of these cases by Zingarelli *at al* involving 27 HBV-infected patients treated with anti-TNF agents, HBV reactivation was documented in 14% of patients treated with lamivudine compared with 73% of patients not receiving HBV prophylaxis (Zingarelli, Frassi et al. 2009) thus suggesting that the use of prophylactic lamivudine could help reducing the risk of HBV reactivation. More recently, interesting data with regards to the relative safety of anti-TNF agents in HBV carriers were presented by Charpin *et al* (Charpin, Guis et al. 2009). Their cohort included 21 patients with serologically cured HBV infection, that is HBsAg –ve plus anti-HBc +ve patients and results were suggestive that anti-TNF therapy appeared to be safe during the a limited follow up period of three years. Nevertheless, about 30% of patients involved in this study had significant lower antibody titers over the follow up period which may be relevant during long-term follow up (Jansen 2010). Similar findings we reported by others over a shorter follow up period of 2 years (Vassilopoulos, Apostolopoulou et al. 2010) yet the decrease in antibody titers observed in the later study was comparable to that observed in a control group of patients treated with MTX alone, indicating no apparent specific effect of anti-TNF on HBV protective immunity.

host immunity through the secretion of chemokines, up-regulation of adhesion molecules and the induction of macrophage apoptosis. While TNF blockers may therefore interfere with these important immune functions, other less predictable immune effects have been seen with these agents. In particular, TNF-blockers have been shown to diminish interferon (IFN)-γ effects and stimulate apoptosis of key immune cells, including monocytes, CD4+ T helper cells and Mtb-reactive CD8+ T cells. Anti-TNF therapy is also associated with increased regulatory T cell (Treg) function, which has been linked with susceptibility to TB (Harris and Keane 2010). TNF-α neutralization in mice has resulted in fatal reactivation of persistent tuberculosis characterized by a moderately increased tissue bacillary burden and severe pulmonic histopathological deterioration that was associated with changes indicative of squamous metaplasia and fluid accumulation in the alveolar space (Mohan, Scanga et al.

Although several studies have attempted to address the risk of postoperative infection, limited statistical precision has been a major concern. The largest study reported a 50% (but not statistically significant) increased risk of surgical site infections for those patients who continued therapy peri-operatively (den Broeder, Creemers et al. 2007). Nevertheless, considering the morbidity of orthopedic surgical site infections (especially prosthesis infections) as compared to a transient surge in disease activity, withholding anti-TNF agents peri-operatively appears to be the most reasonable and prudent approach at present

Reactivation of Hepatitis B (HBV) infection is a well described complication of immunosuppression in the setting of organ transplantation or cancer chemotherapy, occurring in up to 50% of patients where concomitant anti-viral treatment is not applied (Shale, Seow et al. 2010). The use of anti-TNF medications has been reported in isolated case reports, case series and chart reviews with a variety of outcomes ranging from apparent viral clearance to fatal hepatitis. In a comprehensive review of these cases by Zingarelli *at al* involving 27 HBV-infected patients treated with anti-TNF agents, HBV reactivation was documented in 14% of patients treated with lamivudine compared with 73% of patients not receiving HBV prophylaxis (Zingarelli, Frassi et al. 2009) thus suggesting that the use of prophylactic lamivudine could help reducing the risk of HBV reactivation. More recently, interesting data with regards to the relative safety of anti-TNF agents in HBV carriers were presented by Charpin *et al* (Charpin, Guis et al. 2009). Their cohort included 21 patients with serologically cured HBV infection, that is HBsAg –ve plus anti-HBc +ve patients and results were suggestive that anti-TNF therapy appeared to be safe during the a limited follow up period of three years. Nevertheless, about 30% of patients involved in this study had significant lower antibody titers over the follow up period which may be relevant during long-term follow up (Jansen 2010). Similar findings we reported by others over a shorter follow up period of 2 years (Vassilopoulos, Apostolopoulou et al. 2010) yet the decrease in antibody titers observed in the later study was comparable to that observed in a control group of patients treated with MTX alone, indicating no apparent specific effect of anti-TNF

2001).

(Bongartz 2007).

**2.5 Viral infections**

on HBV protective immunity.

**2.4 Postoperative infections**

Anti-TNF therapy for RA in the setting of Hepatitis C (HCV) infection could be of particular interest in light of the existing evidence suggesting a role for inflammatory cytokines including TNF-α in the mediating hepatocyte destruction in chronic CMV (Parke and Reveille 2004). It may therefore carefully assumed that anti-TNF agents may be safer in patients infected with HCV rather than HBV (Shale, Seow et al. 2010) and furthermore this notion has been tested in a phase 2 randomised, double-blind, placebo-controlled study where etanercept given for 24 weeks as adjuvant therapy to interferon and ribavirin was shown to significantly improve virological response among patients with chronic HCV and was associated with decreased incidence of most adverse effects associated with interferon and ribavirin (Zein 2005). Although overall experience to date with anti-TNF agents in the chronic HCV setting suggests an acceptable short-term safety profile (Marotte, Fontanges et al. 2007), long-term issues remain to be clarified.

The safety of anti-TNF therapy in HIV is a controversial subject. TNF inhibition in the setting of HIV induced immunosuppression does not appear appealing in view of the potential role for TNF-α in the host defence against infections. Notably, in an early report, the use of etanercept in HIV positive patient with psoriasis and CD4 count of <200/mm3 was associated with polymicrobial infections prompting termination of the treatment (Aboulafia, Bundow et al. 2000). Subsequent reports though have shown a favourable safety profile (Kaur, Chan et al. 2007; Cepeda, Williams et al. 2008), yet clinical decisions should be taken cautiously; careful consideration of the risks and benefits for the individual patient would be needed and close clinical and virological monitoring should always be warranted.

The safety of TNF inhibitors in patients with herpes virus (HSV) infections has also been considered. In particular the risk of herpes zoster infection in patients with RA is twice as much even in the absence of therapy (Wolfe, Michaud et al. 2006; Smitten, Choi et al. 2007) and severe herpes zoster infections have been reported in randomised controlled trials and their open-label follow up studies in patients with RA receiving the TNF inhibitors infliximab or adalimumab (Lipsky, van der Heijde et al. 2000; Furst, Schiff et al. 2003; Keystone, Kavanaugh et al. 2004; Maini, Breedveld et al. 2004). A study by Strangfeld *et al* (Strangfeld, Listing et al. 2009) addressed the question whether this association actually represents a true association between TNF inhibitors reactivation of latent viral infections or simply reflects the increased risk of herpes zoster infection in RA patients (Bongartz and Orenstein 2009). In this prospective cohort the investigators identified 86 episodes of herpes zoster among 5040 patients from the German biologics register RABBIT, receiving anti-TNF agents or conventional DMARDs. Adjusted for age, RA severity and glucocorticoid use, a significant increased risk was observed for treatment with the monoclonal antibodies (HR, 1.82 [95% CI, 0.73-2.55]), although this risk was lower than the threshold (of 2.5) for clinical significance. No significant associations were found for etanercept use (HR 1.36, 95% CI 0.73-2.55) or for anti-TNF treatment (HR 1.63, 95% CI 0.97-2.74) as a class. Equally important, the incidence rate of multidermatomal and ophthalmic zoster was higher in patients taking TNF inhibitors implying severe disease often requiring hospitalisation (Bongartz and Orenstein 2009). Nevertheless, anti-TNF therapy can generally be restarted following temporary interruption and conventional anti-viral therapy until the skin lesions are completely healed (Wendling, Streit et al. 2008). Isolated varicella infections have also been reported in RA patients receiving anti-TNF therapy (Vonkeman, ten Napel et al. 2004; Choi, Kim et al. 2006; Lee, Kim et al. 2007). Notably the rash in one of these cases was

Infectious Complications of Anti-Tumour Necrosis Factor-α Therapy in Rheumatoid Arthritis 103

risk in patients treated with anti-TNF therapy compared to those treated with conventional DMARDs. Common infections involve sites as the respiratory tract, skin and soft tissue and the urinary tract. The risk of *M. tuberculosis* infection also appear to be increased with the use of these agents and is highest during the first 6 months of therapy, most probably reflecting reactivation of latent TB. Screening patients for exposure risks and latent TB prior to the initiation of anti-TNF therapy and administration of standard chemo-prophylaxis has decreased the incidence of new TB cases. Other opportunistic infections such as histoplasmosis, coccidioidomycosis and leishmaniasis may occur following geographical criteria, indicating increased incidence of these illnesses in endemic areas. In view of the increased infectious risk associated with these agents, we should reiterate the importance of efficient pre-treatment screening and close monitoring of patients throughout their treatment. Physicians should be aware of infectious diseases endemic to their geographic area and be vigilant for unusual presentation of symptoms and signs of infectious illnesses. They should stop biologic therapy when these occur, treat those infectious complications promptly and report such cases to regulatory or public health authorities where appropriate. As new biological agents are developed and reach the market place, large scale post marketing surveillance with registry studies and other observational studies will be

Aboulafia, D. M., Bundow, D., Wilske, K., & Ochs, U. I. (2000). Etanercept for the treatment

Askling, J., & Dixon, W. (2008). The safety of anti-tumour necrosis factor therapy in

Bathon, J. M., Martin, R. W., Fleischmann, R. M., Tesser, J. R., Schiff, M. H., Keystone, E. C.,

Bongartz, T. (2007). Elective orthopedic surgery and perioperative DMARD management: many questions, fewer answers, and some opinions. *J Rheumatol*, 34(4), 653-655. Bongartz, T., & Orenstein, R. (2009). Therapy: The risk of herpes zoster: another cost of anti-

Bongartz, T., Sutton, A. J., Sweeting, M. J., Buchan, I., Matteson, E. L., & Montori, V. (2006).

Breedveld, F. C., Weisman, M. H., Kavanaugh, A. F., Cohen, S. B., Pavelka, K., van

not had previous methotrexate treatment. *Arthritis Rheum,* 54(1), 26-37. Carmona, L., Gomez-Reino, J. J., Rodriguez-Valverde, V., Montero, D., Pascual-Gomez, E.,

effects in randomized controlled trials. *JAMA*, 295(19), 2275-2285.

of human immunodeficiency virus-associated psoriatic arthritis. *Mayo Clin Proc*,

Genovese, M. C., Wasko, M.C., Moreland, L. W., Weaver, A.L., Markenson, J., & Finck, B. K. (2000). A comparison of etanercept and methotrexate in patients with

Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful

Vollenhoven, R., Sharp, J., Perez J. L., & Spencer-Green, G. T. (2006). The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had

Mola, E. M., Carreno , L., & Figueroa, M. (2005). Effectiveness of recommendations

needed to establish the long term safety profile of these novel therapies.

rheumatoid arthritis. *Curr Opin Rheumatol*, 20(2), 138-144.

early rheumatoid arthritis. *N Engl J Med*, 343(22), 1586-1593.

TNF therapy*? Nat Rev Rheumatol*, 5(7), 361-363.

**4. References**

75(10), 1093-1098.

atypical (Choi, Kim et al. 2006) stressing the need for high index of suspicion upon diagnosing primary varicella infection in susceptible patients with atypical skin lesions.

Finally, although a prospective study involving 15 patients with refractory forms of RA under treatment with infliximab (3 mg/kg) did not show evidence of lymphotropic herpesviruses reactivation (CMV, HHV-6, HHV-7, HHV-8, EBV) in RA patients (Torre-Cisneros, Del Castillo et al. 2005), two isolated case reports have associated infliximab with HHV8 related Kaposi's sarcoma (Cohen, Horster et al. 2003) and cytomegalovirus (CMV) retinitis (Haerter, Manfras et al. 2004).

#### **2.6 Response to vaccination**

As patients with RA receiving conventional DMARDs and biologics are at increased risk of vaccine preventable diseases such as respiratory tract infections caused by *H. Influenza* and *S. Pneumoniae*, safety and efficacy evaluation of vaccines in this setting is of paramount importance. The use of TNF inhibitors in particular has raised specific concerns with regards to their potential influence on antibody responses to vaccination. The potential influence of anti-TNF inhibition on the efficacy of influenza vaccination was evaluated in a prospective cohort study involving 149 patients with RA including 50 patients treated with TNF blockers (etanercept or infliximab) in combination with MTX, 62 patients receiving TNF blockers alone or with other DMARDs and 37 patients treated with MTX alone plus 18 healthy controls (Kapetanovic, Saxne et al. 2007). Vaccination with trivalent vaccine resulted in better serological response in RA patients treated with MTX without TNF inhibitors compared with those receiving TNF inhibitors alone or in combination with MTX and/or other DMRDS. Nevertheless, the immune response according to the authors was sufficiently large to warrant influenza vaccination to all RA patients regardless of treatment. Similar results were reported by others (Fomin, Caspi et al. 2006). Equally reassuring were results from studies investigating the efficacy of pmeumococcal vaccine in RA patients receiving anti-TNF therapy. In one study, immune response to 23-valent pneumococcal vaccine was better in patients treated with TNF inhibitors without MTX compared to those treated with TNF inhibitors in combination with MTX or MTX alone. Response rates were 50, 31 and 13% for the TNF inhibition without MTX, TNF inhibition with MTX and MTX groups respectively (Kapetanovic, Saxne et al. 2006). In a different prospective cohort of RA patients receiving either adalimumab or placebo, investigators reported that following pneumococcal vaccination, the percentage of patients achieving a vaccine response were similar in the adalimumab and placebo groups [37.4% and 40.4%, respectively; 95% CI - 16.2%, 10.3%]. Equally similar was the percentage of patients with protective antibody titres in both treatment groups (adalimumab: 85.9%, placebo: 81.7%) (Kaine, Kivitz et al. 2007 ). Thus, anti-TNF therapy should not deter physicians from offering patients with RA vaccination against *H. Influenza* and *S. Pneumoniae*.

#### **3. Conclusions and future directions**

TNF-α blockade strategies have revolutionized the treatment RA, raising though safety concerns with regards to increased risk for infections. Although pre-registration clinical trials for TNF inhibitors showed no clear increased risk for infections, long term clinical trials and post registrations studies have shown a small but consistent increase in infection risk in patients treated with anti-TNF therapy compared to those treated with conventional DMARDs. Common infections involve sites as the respiratory tract, skin and soft tissue and the urinary tract. The risk of *M. tuberculosis* infection also appear to be increased with the use of these agents and is highest during the first 6 months of therapy, most probably reflecting reactivation of latent TB. Screening patients for exposure risks and latent TB prior to the initiation of anti-TNF therapy and administration of standard chemo-prophylaxis has decreased the incidence of new TB cases. Other opportunistic infections such as histoplasmosis, coccidioidomycosis and leishmaniasis may occur following geographical criteria, indicating increased incidence of these illnesses in endemic areas. In view of the increased infectious risk associated with these agents, we should reiterate the importance of efficient pre-treatment screening and close monitoring of patients throughout their treatment. Physicians should be aware of infectious diseases endemic to their geographic area and be vigilant for unusual presentation of symptoms and signs of infectious illnesses. They should stop biologic therapy when these occur, treat those infectious complications promptly and report such cases to regulatory or public health authorities where appropriate. As new biological agents are developed and reach the market place, large scale post marketing surveillance with registry studies and other observational studies will be needed to establish the long term safety profile of these novel therapies.

#### **4. References**

102 Insights and Perspectives in Rheumatology

atypical (Choi, Kim et al. 2006) stressing the need for high index of suspicion upon diagnosing primary varicella infection in susceptible patients with atypical skin lesions.

Finally, although a prospective study involving 15 patients with refractory forms of RA under treatment with infliximab (3 mg/kg) did not show evidence of lymphotropic herpesviruses reactivation (CMV, HHV-6, HHV-7, HHV-8, EBV) in RA patients (Torre-Cisneros, Del Castillo et al. 2005), two isolated case reports have associated infliximab with HHV8 related Kaposi's sarcoma (Cohen, Horster et al. 2003) and cytomegalovirus (CMV)

As patients with RA receiving conventional DMARDs and biologics are at increased risk of vaccine preventable diseases such as respiratory tract infections caused by *H. Influenza* and *S. Pneumoniae*, safety and efficacy evaluation of vaccines in this setting is of paramount importance. The use of TNF inhibitors in particular has raised specific concerns with regards to their potential influence on antibody responses to vaccination. The potential influence of anti-TNF inhibition on the efficacy of influenza vaccination was evaluated in a prospective cohort study involving 149 patients with RA including 50 patients treated with TNF blockers (etanercept or infliximab) in combination with MTX, 62 patients receiving TNF blockers alone or with other DMARDs and 37 patients treated with MTX alone plus 18 healthy controls (Kapetanovic, Saxne et al. 2007). Vaccination with trivalent vaccine resulted in better serological response in RA patients treated with MTX without TNF inhibitors compared with those receiving TNF inhibitors alone or in combination with MTX and/or other DMRDS. Nevertheless, the immune response according to the authors was sufficiently large to warrant influenza vaccination to all RA patients regardless of treatment. Similar results were reported by others (Fomin, Caspi et al. 2006). Equally reassuring were results from studies investigating the efficacy of pmeumococcal vaccine in RA patients receiving anti-TNF therapy. In one study, immune response to 23-valent pneumococcal vaccine was better in patients treated with TNF inhibitors without MTX compared to those treated with TNF inhibitors in combination with MTX or MTX alone. Response rates were 50, 31 and 13% for the TNF inhibition without MTX, TNF inhibition with MTX and MTX groups respectively (Kapetanovic, Saxne et al. 2006). In a different prospective cohort of RA patients receiving either adalimumab or placebo, investigators reported that following pneumococcal vaccination, the percentage of patients achieving a vaccine response were similar in the adalimumab and placebo groups [37.4% and 40.4%, respectively; 95% CI - 16.2%, 10.3%]. Equally similar was the percentage of patients with protective antibody titres in both treatment groups (adalimumab: 85.9%, placebo: 81.7%) (Kaine, Kivitz et al. 2007 ). Thus, anti-TNF therapy should not deter physicians from offering patients with RA

TNF-α blockade strategies have revolutionized the treatment RA, raising though safety concerns with regards to increased risk for infections. Although pre-registration clinical trials for TNF inhibitors showed no clear increased risk for infections, long term clinical trials and post registrations studies have shown a small but consistent increase in infection

retinitis (Haerter, Manfras et al. 2004).

vaccination against *H. Influenza* and *S. Pneumoniae*.

**3. Conclusions and future directions**

**2.6 Response to vaccination**

Infectious Complications of Anti-Tumour Necrosis Factor-α Therapy in Rheumatoid Arthritis 105

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**7**

*Rheumatology Service*

*Spain*

**Pamidronate Treatment in Charcot**

Ivonne Vázquez, Mireia Moreno and Marta Larrosa

**Neuro-Osteoarthropathy: Change in**

**Biochemical Markers of Bone Turnover and**

**Radiographic Outcome After Treatment**

*Hospital of Sabadell, Corporació Sanitària i Universitària Parc Taulí (UAB),*

Charcot neuro-osteoarthropathy (CNO) is a disabling, rapidly progressive destructive arthropathy and a devastating condition in patients with sensitive neuropathy secondary to different diseases such as diabetes mellitus, syringomyelia, polyomielitis, multiple sclerosis or leprosy (Storey, 2004). Diabetes is nowadays the most common cause of neuroarthropathy, with the joints of foot being most frequently affected (Shae & Boulton, 1995). The reported incidence and prevalence of CNO varies between 0,1-0,4% of diabetic population, but the real prevalence of CNO in patients with diabetes mellitus is unknown because many cases are undiagnosed due to a lack of recognition of the clinical symptoms of acute presentation (Bailer & Root, 1947; Fabrin et al., 2000; Klenerman, 1996; Rajbhandari et al., 2002; Sinha et al., 1972). Both type 1 and type 2 diabetic patients are at risk. The majority of patients with CNO are between the fifth and sixth decades although type 1 diabetes present CNO at a younger age and most patients have had diabetes for at least 10 years (Clouse et al., 1974; Cofield et al., 1983; Petrova et al., 2004). Bilateral involvement has been described in up to 30% of patients with CNO affecting the feet (Shae & Boulton, 1995). The basic physiopathologic mechanism of CNO is poorly understood although repetitive trauma and autonomic nervous dysfunction are probably implicated (the neurotraumatic and neurovascular theories). Probably there is a triggering factor including trauma or infection which triggers the onset of an inflammatory cascade which leads to an increased osteoclastic

Although there is no clear evidence, the RANK/RANKL/OPG system may play an important role in the osteolysis seen in the acute CNO. The initial trigger leads to a production of proinflammatory cytokines, including tumor necrosis factor alpha (TNF) and interleukin-1(IL-1). The expression of these cytokines could increase the expression of receptor activator of nuclear factor-B (RANKL), the ligand of receptor activator of NF-kB (RANK), that when activated, stimulates the production of nuclear transcription factor NFkB (NF-kB). When NF-kB is expressed in osteoclast precursors cells, it leads to their differentiation to mature osteoclasts and, in consequence, bone resorption (Jeffcoate et al.,

**1. Introduction**

activity in some predisposed patients.

### **Pamidronate Treatment in Charcot Neuro-Osteoarthropathy: Change in Biochemical Markers of Bone Turnover and Radiographic Outcome After Treatment**

Ivonne Vázquez, Mireia Moreno and Marta Larrosa *Hospital of Sabadell, Corporació Sanitària i Universitària Parc Taulí (UAB), Rheumatology Service Spain*

#### **1. Introduction**

108 Insights and Perspectives in Rheumatology

van der Heijde, D., Klareskog, L., Rodriguez-Valverde, V., Codreanu, C., Bolosiu, H., Melo-

study, a double-blind, randomized trial. *Arthritis Rheum*, 54(4), 1063-1074. van Riel, P. L., Taggart, A. J., Sany, J., Gaubitz, M., Nab, H. W., Pedersen, R., Freundlich, B.,

Vassilopoulos, D., Apostolopoulou, A., Hadziyannis, E., Papatheodoridis, G. V.,

Weinblatt, M. E., Keystone, E. C., Furst, D. E., Kavanaugh, A. F., Chartash, E. K., &

Weinblatt, M. E., Keystone, E. C., Furst, D. E., Moreland, L. W., Weisman, M. H., Birbara, C.

Wendling, D., Streit, G., Toussirot, E., & Prati, C. (2008). Herpes zoster in patients taking

Winthrop, K. L., & Chiller, T. (2009). Preventing and treating biologic-associated

Wolfe, F., Michaud, K., & Chakravarty, E. F. (2006). Rates and predictors of herpes zoster in

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Zingarelli, S., Frassi, M., Bazzani, C., Scarsi, M., Puoti, M., & Airo, P. (2009). Use of tumor

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Gomes, J., Tornero-Molina, J., Wajdula, J., Pedersen, R., & Fatenejad, S. (2006). Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO

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necrosis factor-alpha-blocking agents in hepatitis B virus-positive patients: reports

Charcot neuro-osteoarthropathy (CNO) is a disabling, rapidly progressive destructive arthropathy and a devastating condition in patients with sensitive neuropathy secondary to different diseases such as diabetes mellitus, syringomyelia, polyomielitis, multiple sclerosis or leprosy (Storey, 2004). Diabetes is nowadays the most common cause of neuroarthropathy, with the joints of foot being most frequently affected (Shae & Boulton, 1995). The reported incidence and prevalence of CNO varies between 0,1-0,4% of diabetic population, but the real prevalence of CNO in patients with diabetes mellitus is unknown because many cases are undiagnosed due to a lack of recognition of the clinical symptoms of acute presentation (Bailer & Root, 1947; Fabrin et al., 2000; Klenerman, 1996; Rajbhandari et al., 2002; Sinha et al., 1972). Both type 1 and type 2 diabetic patients are at risk. The majority of patients with CNO are between the fifth and sixth decades although type 1 diabetes present CNO at a younger age and most patients have had diabetes for at least 10 years (Clouse et al., 1974; Cofield et al., 1983; Petrova et al., 2004). Bilateral involvement has been described in up to 30% of patients with CNO affecting the feet (Shae & Boulton, 1995). The basic physiopathologic mechanism of CNO is poorly understood although repetitive trauma and autonomic nervous dysfunction are probably implicated (the neurotraumatic and neurovascular theories). Probably there is a triggering factor including trauma or infection which triggers the onset of an inflammatory cascade which leads to an increased osteoclastic activity in some predisposed patients.

Although there is no clear evidence, the RANK/RANKL/OPG system may play an important role in the osteolysis seen in the acute CNO. The initial trigger leads to a production of proinflammatory cytokines, including tumor necrosis factor alpha (TNF) and interleukin-1(IL-1). The expression of these cytokines could increase the expression of receptor activator of nuclear factor-B (RANKL), the ligand of receptor activator of NF-kB (RANK), that when activated, stimulates the production of nuclear transcription factor NFkB (NF-kB). When NF-kB is expressed in osteoclast precursors cells, it leads to their differentiation to mature osteoclasts and, in consequence, bone resorption (Jeffcoate et al.,

Pamidronate Treatment in Charcot Neuro-Osteoarthropathy:

(Aliadabi et al., 2003; Jones et al., 2000).

dislocation of the affected bones.

**2.2 Radionucleide scintigraphy**

**2.3 Magnetic resonance imaging**

Change in Biochemical Markers of Bone Turnover and Radiographic Outcome After Treatment 111

Medical literature focused on radiology findings describe two patterns of CNO: a hypertrophic pattern characterized by joint destruction and bone fragmentation, debris formation, sclerosis and osteophytosis, such as osteoarthritis and an atrophic pattern showing osseous resorption and joint disorganization that may appear similar to septic arthritis, so, differential diagnosis between atrophic CNO and septic arthritis may be difficult. Frequently, patients present a combination of hypertrophic and atrophic patterns

In the diabetic population, destructive or resorptive bony abnormalities can predominate depending on the location of CNO. At the mid-foot or tarsometatarsal joints (Lisfranc) [the most common localization representing about 60%(Brodsky)], bone fragmentation, sclerosis with fracture-dislocation and complete disintegration of one or more tarsal bone are frequently found. This may lead to a collapse of the longitudinal arch and increased load bearing on the cuboid, resulting in a "rocker-bottom" deformity. If the metatarsophalangeal joints are affected, bone resorption is the predominant feature, leading to a disappearance, partial or complete, of the metatarsal heads and proximal phalanges. Finally, the hindfoot and ankle, although less frequent, it may be affected with fragmentation, eburnation and

In summary, the five D's describe the radiological features of CNO: joint distension, dislocations, debris, disorganization and increased density (Rajbhandari et al., 2002), being

Three imaging phases 99Technetium bone scan (99Tc-scan) are highly sensitive (91%) for osseus pathology but lacks specificity (54%) for the diagnosis of CNO (Aliadabi et al., 2003; Sella, 2009; Schauwecker et al., 1988). The scintigraphy is positive in all 3 phases, reflecting an increased bone turnover, a similar situation to that found in other conditions such as osteomyelitis. In these cases, in order to improve the specificity of the test to rule out infection the labeled white cell scans (99Tc-WBC, HMPAO, 111In-WBC) can be used. These scintigraphy techniques show increased activity at the site of infection, reaching a specificity of 60-86%

A fourth phase or 24-hour phase image 99Tc-scan can be used to improve the localization of

The 67Ga/bone imaging study is not reliable for diagnosing osteomyelitis because 67Ga also

Given its high sensitivity, the scintigraphy may be useful in early diagnosis although can not rule out the presence of a coexisting infection. However it has two major limitations: sometimes may not differentiate bone infection from that of adjacent soft tissues due to low

The role of MRI for diagnostic imaging of the diabetic foot is increasing due to its advantages over scintigraphy and radiographs but its use is still unclear.The T1-weighted

the presence of multiples fractures the most suggestive radiologic pattern of CNO.

depending on the studies and on the radiotracer used to label white cells (Sella, 2009).

the affected site when there is too much background activity.

accumulates in sterile CNO (Glynn, 1981; Knight et al. 1988).

resolution, and the presence of peripheral ischemia can limit sensitivity.

2005; Jeffcoate, 2008; Molines et al., 2010). In this sense, Mabilleau et al. studied isolated peripheral blood monocytes from diabetic Charcot patients, diabetic controls and healthy controls and demonstrated that resorption in acute CNO is related to an increase in RANKLmediated osteoclastic activity (Mabilleau et al., 2008).

The usual initial presentation of acute CNO is a swelling, tender and warm involved joint and there is usually a temperature difference greater than 2ºC when compared with the contralateral joint (Jude & Boulton, 2001; Petrova & Edmonds, 2008). The whole clinical picture can simulate an infection in its appearance. The chronic CNO is painless, without a temperature difference and characterized by established deformity.

The aim of this chapter is to review the usefulness of biochemical bone markers and the image features for both diagnosis and for follow-up after treatment of CNO with bisphosphonates (pamidronate).

#### **2. Imaging and biochemical markers of turnover in diagnosis of Charcot neuro-osteoarthropathy**

Although the diagnostic is based on clinical findings, conventional radiography, radionucleide scintigraphy and magnetic resonance imaging (MRI) are the more common modalities used for helping to the diagnosis of CNO.

#### **2.1 Plain radiography**

X-plain radiographs are usually the first exam used and they are useful for anatomical information. However they are neither sensitive nor specific to differentiate acute CNO changes from osteomyelitis.

In early stages, the presence of effusion with minimal subluxation and fracture-bone fragmentation should alert to the physician to the possibility of CNO. These initial changes may progress to collapse, resorption and subchondral bone fragmentation, bone proliferation with sclerosis and osteophytosis, intra-articular bone fragments, complete subluxation, massive soft tissue enlargement and effusion and fracture of neighboring bones (Resnick & Niwayama).

The Eichenholtz classification (Eichenholtz, 1966) modified by Shibata et al. (Shibata et al., 1990) describe a correlation between clinical findings and radiographic features (table 1).

Table 1. Eichenholtz classification modified by Shibata.

Medical literature focused on radiology findings describe two patterns of CNO: a hypertrophic pattern characterized by joint destruction and bone fragmentation, debris formation, sclerosis and osteophytosis, such as osteoarthritis and an atrophic pattern showing osseous resorption and joint disorganization that may appear similar to septic arthritis, so, differential diagnosis between atrophic CNO and septic arthritis may be difficult. Frequently, patients present a combination of hypertrophic and atrophic patterns (Aliadabi et al., 2003; Jones et al., 2000).

In the diabetic population, destructive or resorptive bony abnormalities can predominate depending on the location of CNO. At the mid-foot or tarsometatarsal joints (Lisfranc) [the most common localization representing about 60%(Brodsky)], bone fragmentation, sclerosis with fracture-dislocation and complete disintegration of one or more tarsal bone are frequently found. This may lead to a collapse of the longitudinal arch and increased load bearing on the cuboid, resulting in a "rocker-bottom" deformity. If the metatarsophalangeal joints are affected, bone resorption is the predominant feature, leading to a disappearance, partial or complete, of the metatarsal heads and proximal phalanges. Finally, the hindfoot and ankle, although less frequent, it may be affected with fragmentation, eburnation and dislocation of the affected bones.

In summary, the five D's describe the radiological features of CNO: joint distension, dislocations, debris, disorganization and increased density (Rajbhandari et al., 2002), being the presence of multiples fractures the most suggestive radiologic pattern of CNO.

#### **2.2 Radionucleide scintigraphy**

110 Insights and Perspectives in Rheumatology

2005; Jeffcoate, 2008; Molines et al., 2010). In this sense, Mabilleau et al. studied isolated peripheral blood monocytes from diabetic Charcot patients, diabetic controls and healthy controls and demonstrated that resorption in acute CNO is related to an increase in RANKL-

The usual initial presentation of acute CNO is a swelling, tender and warm involved joint and there is usually a temperature difference greater than 2ºC when compared with the contralateral joint (Jude & Boulton, 2001; Petrova & Edmonds, 2008). The whole clinical picture can simulate an infection in its appearance. The chronic CNO is painless, without a

The aim of this chapter is to review the usefulness of biochemical bone markers and the image features for both diagnosis and for follow-up after treatment of CNO with

Although the diagnostic is based on clinical findings, conventional radiography, radionucleide scintigraphy and magnetic resonance imaging (MRI) are the more common

X-plain radiographs are usually the first exam used and they are useful for anatomical information. However they are neither sensitive nor specific to differentiate acute CNO

In early stages, the presence of effusion with minimal subluxation and fracture-bone fragmentation should alert to the physician to the possibility of CNO. These initial changes may progress to collapse, resorption and subchondral bone fragmentation, bone proliferation with sclerosis and osteophytosis, intra-articular bone fragments, complete subluxation, massive soft tissue enlargement and effusion and fracture of neighboring bones

The Eichenholtz classification (Eichenholtz, 1966) modified by Shibata et al. (Shibata et al., 1990) describe a correlation between clinical findings and radiographic features (table 1).

> acute symptoms osteopenia, bone destruction, debris formation,

> > ,dislocations

decreased symptoms resorption of debris, bony sclerosis ,

resolved bony remodeling, rounding of fragments

fusion of bone fragments

fragmentation of the subchondral bone , capsular distention, subluxations

**2. Imaging and biochemical markers of turnover in diagnosis of Charcot**

mediated osteoclastic activity (Mabilleau et al., 2008).

modalities used for helping to the diagnosis of CNO.

Stage 0 early phase acute symptoms no changes

Table 1. Eichenholtz classification modified by Shibata.

bisphosphonates (pamidronate).

**neuro-osteoarthropathy**

**2.1 Plain radiography**

changes from osteomyelitis.

(Resnick & Niwayama).

Stage 1 development stage

Stage 2 coalescence stage

Stage 3 reconstruction stage

temperature difference and characterized by established deformity.

Three imaging phases 99Technetium bone scan (99Tc-scan) are highly sensitive (91%) for osseus pathology but lacks specificity (54%) for the diagnosis of CNO (Aliadabi et al., 2003; Sella, 2009; Schauwecker et al., 1988). The scintigraphy is positive in all 3 phases, reflecting an increased bone turnover, a similar situation to that found in other conditions such as osteomyelitis. In these cases, in order to improve the specificity of the test to rule out infection the labeled white cell scans (99Tc-WBC, HMPAO, 111In-WBC) can be used. These scintigraphy techniques show increased activity at the site of infection, reaching a specificity of 60-86% depending on the studies and on the radiotracer used to label white cells (Sella, 2009).

A fourth phase or 24-hour phase image 99Tc-scan can be used to improve the localization of the affected site when there is too much background activity.

The 67Ga/bone imaging study is not reliable for diagnosing osteomyelitis because 67Ga also accumulates in sterile CNO (Glynn, 1981; Knight et al. 1988).

Given its high sensitivity, the scintigraphy may be useful in early diagnosis although can not rule out the presence of a coexisting infection. However it has two major limitations: sometimes may not differentiate bone infection from that of adjacent soft tissues due to low resolution, and the presence of peripheral ischemia can limit sensitivity.

#### **2.3 Magnetic resonance imaging**

The role of MRI for diagnostic imaging of the diabetic foot is increasing due to its advantages over scintigraphy and radiographs but its use is still unclear.The T1-weighted

Pamidronate Treatment in Charcot Neuro-Osteoarthropathy:

Low intensity T1-

Distribution Focal bone involvement Several bone affected

Table 2. Differential MRI patterns between osteomyelitis and Charcot neuro-

have been also demonstrated in CNO patients (Edelson et al., 1996).

the role of bone markers for the diagnosis is yet to be determined.

**of Charcot neuro-osteoarthropathy**

Deformity Not common Common

**Soft tissue features** Frequently involved: sinus tracts, cellulitis, abscess

**2.4 Biochemical markers of bone turnover**

**Bone features**

and STIR-

Low intensity T1- High intensity T2-

Bone marrow

osteoarthropathy.

Change in Biochemical Markers of Bone Turnover and Radiographic Outcome After Treatment 113

Diffuse edema Periarticular and subcondral edema

Weight bearing regions Predominant midfoot involvement

Biochemical markers of bone turnover are often altered in CNO. There are few studies done, most of them evaluating the changes of these markers after treatment, mainly bisphosphonates. Some studies on bone turnover markers show an increase of these parameters in acute CNO, indicating an unspecific increased in bone activity. Gough et al. measured the pyridoline cross-linked carboxy-terminal telopeptide domain of type 1 collagen (1CTP) and carboxy-terminal propeptide of type 1 collagen (P1CP), both validated as markers of bone resorption and formation respectively, in diabetic patients with acute CNO, chronic CNO, diabetic controls and non-diabetic controls subjects (Gough et al., 1997). Serum 1CTP was significantly raised in the dorsal venous arch of the acute CNO feet compared to chronic CNO, diabetic controls and non-diabetic controls. The authors did not find any significant difference in serum P1CP levels in any group. These levels of 1CTP and P1CP suggest an increase in osteoclastic activity without concomitant increase of osteoblastic function. Selby et al. found an increase in bone-specific alkaline phosphatase (bone formation marker) with no significant changes among the others biochemical parameters studied: osteocalcin, urinary hydroxyproline, urinary desoxypyridinoline ( Selby et al., 1998). Increased levels of urinary cross-linked N-telopeptides of type 1 collagen (NTX)

In summary, there are few studies focused on bone markers in CNO. The data suggest an increase of them in acute CNO especially of resorption parameters. However, it seems that

**3. Imaging and biochemical markers of bone turnover after medical treatment**

Although the cornerstone of treatment of CNO is immobilization, there are some studies that demonstrate the clinical benefit of bisphosphonates. The improvement with bisphosphonates appears to be sooner compared to patients with conventional therapy

**Osteomyelitis Charcot Neuro-osteoarthropathy**

**Acute CNO Chronic CNO**

Low intensity T1- Low intensity T2 and STIR-

High intensity T2-

Infrequently involved

and STIR-

sequences show anatomical references, both normal or abnormal, while T2- and STIR- (short tau inversion recovery) weighted sequences are better to demonstrate edema and inflammatory changes in the soft tissues and bone.

Some possible algorithms have been proposed (Giurato & Uccioli, 2006) but it is usually considered that MRI is not necessary in patients with evidence of CNO on plain radiographs and no clinical signs of infection (Giurato & Uccioli, 2006; Marcus et al., 1996).

CNO may present with two types of changes on MRI, depending on the evolution time of the process. Acute CNO shows a low signal intensity within bone marrow on T1-weighted sequences and high signal intensity on T2- and STIR-weighted sequences, findings that are similar to those observed in osteomyelitis. In a chronic CNO, besides cortical fragmentation, joint deformity and dislocation, typically appears a low signal intensity in the bone marrow on both T1- and T2-weighted sequences consistent with osteosclerosis on plain radiography. Another finding in chronic CNO is cyst-like lesions in the bone marrow which appear as well-defined clearly marginated low signal lesions on T1-weighted images and as high signal intensity on T2-weighted images (Beltran et al. 1990; Marcus et al., 1996).

MRI may also be useful to early diagnosis when patients present acute symptoms and no changes in plain radiographs can be detected (stage 0 of Eichenholtz classification). In these cases, MRI may detect early events, such as bone edema, occult fractures and joint effusion (Chantelau & Poll, 2006; Edmonds et al., 2006; Greenstein et al., 2002).

Bone and soft tissue infection involving the foot is particularly common in patients with diabetes mellitus, and in these patients, CNO often coexists. The differentiation between these two entities is difficult. There are some MRI features that help to differentiate acute CNO from osteomyelitis: bone marrow signal damage and edema pattern, distribution of the changes, presence of deformity and soft tissue changes (ulcers, abscess or sinus tracts) (Lederman & Morrison, 2005; Lederman et al., 2002; Tan & Teh, 2007). Ahmadi et al., in a retrospective review of contrast-enhanced MRI study of 128 neuropathic feet joints in 63 diabetic patients with a suspicion of osteomyelitis, found that the presence of sinus tract, the presence of soft-tissue fluid collection and extensive bone marrow abnormality were MRI features commonly present in a superimposed infection (Ahmadi et al., 2006) (table 2).

Several studies demonstrate that MRI has a high sensitivity (77-100%) and specificity (80- 100%) for osteomyelitis. Furthermore, in osteomyelitis MRI has a positive predictive power of 93% and almost a negative predictive power of 100% according to studies that compared MRI results to bone biopsy, which is considered the gold standard for diagnosing osteomyelitis (Levine et al., 1994; Marcus et al., 1996). However there are no studies assessing neither the sensitivity nor specificity of MRI detecting osteomyelitis in CNO patients.

The use of gadolinium in CNO is controversial (Marcus et al.,1996; Morrison et al., 1993) although may be useful to complete the soft tissue study (abscesses, sinus tracts, cellulitis).

In summary, MRI is a useful, non-invasive tool for the early diagnosis of CNO and may have utility for detecting a superimposed infection, being the soft tissue alteration the most specific finding.

Table 2. Differential MRI patterns between osteomyelitis and Charcot neuroosteoarthropathy.

#### **2.4 Biochemical markers of bone turnover**

112 Insights and Perspectives in Rheumatology

sequences show anatomical references, both normal or abnormal, while T2- and STIR- (short tau inversion recovery) weighted sequences are better to demonstrate edema and

Some possible algorithms have been proposed (Giurato & Uccioli, 2006) but it is usually considered that MRI is not necessary in patients with evidence of CNO on plain radiographs

CNO may present with two types of changes on MRI, depending on the evolution time of the process. Acute CNO shows a low signal intensity within bone marrow on T1-weighted sequences and high signal intensity on T2- and STIR-weighted sequences, findings that are similar to those observed in osteomyelitis. In a chronic CNO, besides cortical fragmentation, joint deformity and dislocation, typically appears a low signal intensity in the bone marrow on both T1- and T2-weighted sequences consistent with osteosclerosis on plain radiography. Another finding in chronic CNO is cyst-like lesions in the bone marrow which appear as well-defined clearly marginated low signal lesions on T1-weighted images and as high

MRI may also be useful to early diagnosis when patients present acute symptoms and no changes in plain radiographs can be detected (stage 0 of Eichenholtz classification). In these cases, MRI may detect early events, such as bone edema, occult fractures and joint effusion

Bone and soft tissue infection involving the foot is particularly common in patients with diabetes mellitus, and in these patients, CNO often coexists. The differentiation between these two entities is difficult. There are some MRI features that help to differentiate acute CNO from osteomyelitis: bone marrow signal damage and edema pattern, distribution of the changes, presence of deformity and soft tissue changes (ulcers, abscess or sinus tracts) (Lederman & Morrison, 2005; Lederman et al., 2002; Tan & Teh, 2007). Ahmadi et al., in a retrospective review of contrast-enhanced MRI study of 128 neuropathic feet joints in 63 diabetic patients with a suspicion of osteomyelitis, found that the presence of sinus tract, the presence of soft-tissue fluid collection and extensive bone marrow abnormality were MRI features commonly present in a superimposed infection (Ahmadi et al., 2006)

Several studies demonstrate that MRI has a high sensitivity (77-100%) and specificity (80- 100%) for osteomyelitis. Furthermore, in osteomyelitis MRI has a positive predictive power of 93% and almost a negative predictive power of 100% according to studies that compared MRI results to bone biopsy, which is considered the gold standard for diagnosing osteomyelitis (Levine et al., 1994; Marcus et al., 1996). However there are no studies assessing neither the sensitivity nor specificity of MRI detecting osteomyelitis in CNO

The use of gadolinium in CNO is controversial (Marcus et al.,1996; Morrison et al., 1993) although may be useful to complete the soft tissue study (abscesses, sinus tracts, cellulitis). In summary, MRI is a useful, non-invasive tool for the early diagnosis of CNO and may have utility for detecting a superimposed infection, being the soft tissue alteration the most

and no clinical signs of infection (Giurato & Uccioli, 2006; Marcus et al., 1996).

signal intensity on T2-weighted images (Beltran et al. 1990; Marcus et al., 1996).

(Chantelau & Poll, 2006; Edmonds et al., 2006; Greenstein et al., 2002).

(table 2).

patients.

specific finding.

inflammatory changes in the soft tissues and bone.

Biochemical markers of bone turnover are often altered in CNO. There are few studies done, most of them evaluating the changes of these markers after treatment, mainly bisphosphonates. Some studies on bone turnover markers show an increase of these parameters in acute CNO, indicating an unspecific increased in bone activity. Gough et al. measured the pyridoline cross-linked carboxy-terminal telopeptide domain of type 1 collagen (1CTP) and carboxy-terminal propeptide of type 1 collagen (P1CP), both validated as markers of bone resorption and formation respectively, in diabetic patients with acute CNO, chronic CNO, diabetic controls and non-diabetic controls subjects (Gough et al., 1997). Serum 1CTP was significantly raised in the dorsal venous arch of the acute CNO feet compared to chronic CNO, diabetic controls and non-diabetic controls. The authors did not find any significant difference in serum P1CP levels in any group. These levels of 1CTP and P1CP suggest an increase in osteoclastic activity without concomitant increase of osteoblastic function. Selby et al. found an increase in bone-specific alkaline phosphatase (bone formation marker) with no significant changes among the others biochemical parameters studied: osteocalcin, urinary hydroxyproline, urinary desoxypyridinoline ( Selby et al., 1998). Increased levels of urinary cross-linked N-telopeptides of type 1 collagen (NTX) have been also demonstrated in CNO patients (Edelson et al., 1996).

In summary, there are few studies focused on bone markers in CNO. The data suggest an increase of them in acute CNO especially of resorption parameters. However, it seems that the role of bone markers for the diagnosis is yet to be determined.

#### **3. Imaging and biochemical markers of bone turnover after medical treatment of Charcot neuro-osteoarthropathy**

Although the cornerstone of treatment of CNO is immobilization, there are some studies that demonstrate the clinical benefit of bisphosphonates. The improvement with bisphosphonates appears to be sooner compared to patients with conventional therapy

Pamidronate Treatment in Charcot Neuro-Osteoarthropathy:

disease in most cases.

Change in Biochemical Markers of Bone Turnover and Radiographic Outcome After Treatment 115

Patients included in this protocol received three intravenous infusions of pamidronate at 0, 2 and 4 months and traditional immobilization methods. Two diabetic patients had a concomitant septic arthritis in the affected joint and they received also antibiotic treatment. Biochemical markers of bone remodeling, radiological exam and 99Tc-scan were performed before and after 12 months treatment. The bone remodeling markers study included blood alkaline phosphatase (ALP) and BSAP, urinary crosslinks NTX, pyridoline (pyr) and D-pyr. Clinical symptoms improved after the first infusion. Although in most cases the bone basal remodeling markers were within normal range values, a clear decrease in almost all of these remodeling markers was observed after treatment in all patients, reaching statistical significance for NTX and urinary pyr, suggesting that the blocking of the osteoclastic activity may play an important role in the physiopathology of CNO, as observed in previous studies. All patients, except one with a siringomyelia, showed signs of radiological healing with a marked sclerosis and reconstruction of the cortical bone (figure 1). In one case pamidronate was administered very early, avoiding the progression and preventing the occurrence of radiological changes during the follow-up period (figure 2). Quantitative scintigraphy was performed only in 3 cases, showing a decrease in radiotracer uptake after treatment although it did not become completely normal. In agreement with previous studies, pamidronate improved not only clinical signs but also stopped the progression of

Before treatment After treatment

Fig. 1. Patient with a Charcot foot and concomitant septic arthritis. Note before pamidronate treatment the presence of bone fragmentation, subluxation, loss of defined contours and

eburnation and after 6-months treatment sclerosis and defined contours.

(immobilization) (Anderson et al., 2004). Most studies use pamidronate, although alendronate has been demonstrated to be useful in one study (Pitocco et al., 2005). The optimal treatment regimen of pamidronate remains to be defined. Multiples observational studies have been published using different doses and duration, and all of them have demonstrated some clinical improvement (Navqi et al., 2008; Selby et al., 1994; Young, 1999). Furthermore, some reports have also shown an improvement in radiological changes (Guis et al., 1999) and/or decrease of biochemical bone turnover markers.

Jude et al. published the first trial of pharmacologic treatment, a randomized, doubleblinded, placebo-controlled study in 39 active CNO patients (Jude et al., 2001). Twenty-one patients recieved a single infusion of 90 mg of pamidronate and this group showed a significantly reduction in all biochemical markers analized (bone-specific alkaline phosphatase (BSAP) and urine deoxypyridoline cross-linked (D-pyr)) that persisted until 24 weeks in the case of BSAP. However, after 12 months follow-up, both biomarkers rose toward baseline levels.

Comparable results were obtained in 11 patients during treatment with alendronate 70 mg once a week over 6 months, in a randomized controlled double blind study. A clinical improvement was observed and, 1CTP and urinary hydroxyproline levels, as indicators of bone resorption, showed a significant decrease in the treated group after treatment (Pitocco et al., 2005).

Some case reports have demonstrated healing or stabilization of changes on plain radiography after intravenous pamidronate (Guis et al., 1999; Naqvi et al., 2008; Young, 1999).

In a short communication, Mc Gill et al. reported that bone uptake scintigraphy and skin temperature improved over 12 months with immobilization (McGill et al., 2000), but there are no studies evaluating changes in neither MRI nor bone scintigraphy after bisphosphonate treatment.

Bem and collages determined quantitative bone scan parameters (ratio of foot and wholebody uptake and blood flow velocity) and markers of bone turnover (1CTP and BSAP) in 42 CNO patients (21 with acute and 21 with non-acute CNO) (Bem et al., 2010). The authors observed that there was a significant correlation between bone scintigraphy parameters and bone turnover markers. In addition, in acute CNO, there was a significant reduction of both scintigraphy parameters and levels of 1CTP and BSAP after treatment with calcitonin.

Schlossbauer and col. published the first report on quantitative assessment of signal alterations on constrast-enhanced MRI in CNO stage 0, before and after treatment with pressure-relieving means (Schlossbauer et al., 2008). In this study they analyzed the clinical symptoms of 13 patients with acute CNO and compared with MRI findings at baseline and after 4-month follow-up. They found a significant correlation between bone marrow edema and soft tissue edema and pain, with a significant decrease of these parameters after treatment. Thus, they concluded that MRI in early stage of CNO provides valuable information on the activity of the disease.

Our group published an open, prospective therapeutical study with a 12-month follow-up including 7 consecutive patients (four diabetic, two with syringomielia and one with an autonomic neuropathy) with active CNO seen over a period of 3 years (Moreno et al., 2007). Patients included in this protocol received three intravenous infusions of pamidronate at 0, 2 and 4 months and traditional immobilization methods. Two diabetic patients had a concomitant septic arthritis in the affected joint and they received also antibiotic treatment. Biochemical markers of bone remodeling, radiological exam and 99Tc-scan were performed before and after 12 months treatment. The bone remodeling markers study included blood alkaline phosphatase (ALP) and BSAP, urinary crosslinks NTX, pyridoline (pyr) and D-pyr. Clinical symptoms improved after the first infusion. Although in most cases the bone basal remodeling markers were within normal range values, a clear decrease in almost all of these remodeling markers was observed after treatment in all patients, reaching statistical significance for NTX and urinary pyr, suggesting that the blocking of the osteoclastic activity may play an important role in the physiopathology of CNO, as observed in previous studies. All patients, except one with a siringomyelia, showed signs of radiological healing with a marked sclerosis and reconstruction of the cortical bone (figure 1). In one case pamidronate was administered very early, avoiding the progression and preventing the occurrence of radiological changes during the follow-up period (figure 2). Quantitative scintigraphy was performed only in 3 cases, showing a decrease in radiotracer uptake after treatment although it did not become completely normal. In agreement with previous studies, pamidronate improved not only clinical signs but also stopped the progression of disease in most cases.

#### Before treatment After treatment

114 Insights and Perspectives in Rheumatology

(immobilization) (Anderson et al., 2004). Most studies use pamidronate, although alendronate has been demonstrated to be useful in one study (Pitocco et al., 2005). The optimal treatment regimen of pamidronate remains to be defined. Multiples observational studies have been published using different doses and duration, and all of them have demonstrated some clinical improvement (Navqi et al., 2008; Selby et al., 1994; Young, 1999). Furthermore, some reports have also shown an improvement in radiological changes (Guis

Jude et al. published the first trial of pharmacologic treatment, a randomized, doubleblinded, placebo-controlled study in 39 active CNO patients (Jude et al., 2001). Twenty-one patients recieved a single infusion of 90 mg of pamidronate and this group showed a significantly reduction in all biochemical markers analized (bone-specific alkaline phosphatase (BSAP) and urine deoxypyridoline cross-linked (D-pyr)) that persisted until 24 weeks in the case of BSAP. However, after 12 months follow-up, both biomarkers rose

Comparable results were obtained in 11 patients during treatment with alendronate 70 mg once a week over 6 months, in a randomized controlled double blind study. A clinical improvement was observed and, 1CTP and urinary hydroxyproline levels, as indicators of bone resorption, showed a significant decrease in the treated group after treatment (Pitocco

Some case reports have demonstrated healing or stabilization of changes on plain radiography after intravenous pamidronate (Guis et al., 1999; Naqvi et al., 2008; Young,

In a short communication, Mc Gill et al. reported that bone uptake scintigraphy and skin temperature improved over 12 months with immobilization (McGill et al., 2000), but there are no studies evaluating changes in neither MRI nor bone scintigraphy after

Bem and collages determined quantitative bone scan parameters (ratio of foot and wholebody uptake and blood flow velocity) and markers of bone turnover (1CTP and BSAP) in 42 CNO patients (21 with acute and 21 with non-acute CNO) (Bem et al., 2010). The authors observed that there was a significant correlation between bone scintigraphy parameters and bone turnover markers. In addition, in acute CNO, there was a significant reduction of both scintigraphy parameters and levels of 1CTP and BSAP after treatment with calcitonin.

Schlossbauer and col. published the first report on quantitative assessment of signal alterations on constrast-enhanced MRI in CNO stage 0, before and after treatment with pressure-relieving means (Schlossbauer et al., 2008). In this study they analyzed the clinical symptoms of 13 patients with acute CNO and compared with MRI findings at baseline and after 4-month follow-up. They found a significant correlation between bone marrow edema and soft tissue edema and pain, with a significant decrease of these parameters after treatment. Thus, they concluded that MRI in early stage of CNO provides valuable

Our group published an open, prospective therapeutical study with a 12-month follow-up including 7 consecutive patients (four diabetic, two with syringomielia and one with an autonomic neuropathy) with active CNO seen over a period of 3 years (Moreno et al., 2007).

et al., 1999) and/or decrease of biochemical bone turnover markers.

toward baseline levels.

bisphosphonate treatment.

information on the activity of the disease.

et al., 2005).

1999).

Fig. 1. Patient with a Charcot foot and concomitant septic arthritis. Note before pamidronate treatment the presence of bone fragmentation, subluxation, loss of defined contours and eburnation and after 6-months treatment sclerosis and defined contours.

Pamidronate Treatment in Charcot Neuro-Osteoarthropathy:

condition quite common in diabetic patients

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108A.

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also for disease outcome

pp. 622-631.

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Change in Biochemical Markers of Bone Turnover and Radiographic Outcome After Treatment 117

 biomarkers of bone turnover are increased in acute phase, especially resorptive ones. However, their utility for monitoring treatment response remains to be established bisphosphonate treatment appears to be effective not only for clinical improvement but

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early diagnosis and treatment may be important to avoid late structural damage

Fig. 2. Patient with a known CNO secondary to syringomielia involving 1st right MCP (arrow). She developed a 3rd MCP swelling joint, early detected with scintigraphy. Initial radiography did not show any changes. Treatment was administered very early avoiding established deformities.

#### **4. Conclusions**

early diagnosis in CNO is difficult and needs a high index of suspicion

#### **5. References**

116 Insights and Perspectives in Rheumatology

Fig. 2. Patient with a known CNO secondary to syringomielia involving 1st right MCP (arrow). She developed a 3rd MCP swelling joint, early detected with scintigraphy. Initial radiography did not show any changes. Treatment was administered very early avoiding

Before treatment After treatment

early diagnosis in CNO is difficult and needs a high index of suspicion

established deformities.

**4. Conclusions**

Pamidronate Treatment in Charcot Neuro-Osteoarthropathy:

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**Part 2**

**Sjögren's Syndrome:**

**Clinical and Immunological Aspects**

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## **Part 2**

**Sjögren's Syndrome: Clinical and Immunological Aspects**

120 Insights and Perspectives in Rheumatology

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change. *Br J Radiol*, Vol. 80, No. 959, (November), pp. 939-948.

210.

**8**

**Diagnostic and Prognostic Features**

Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by the lymphocytic infiltration of salivary and lacrymal glands leading to xerostomia and keratoconjunctivitis sicca (KCS). The prevalence of SS is variable but recent studies have estimated it to be between 0.1-0.6%(Goransson et al., 2011; Trontzas & Andrianakos, 2005). As such, SS occurs in middleaged patients with a high female predominance of 9 to 1 (Fox, 2005). SS is classified either as primary (pSS) when occurring alone or secondary (sSS) to other autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus. Besides the involvement of exocrine glands entailing the classical sicca syndrome, systemic manifestations resulting from the lymphocytic infiltration of organs can be present in up to 20% of cases. There are actually no specific diagnostic criteria for SS, but for clinical studies and teaching purposes, SS is classified according to the American-European classification criteria, which include subjective and objective criteria of xerostomia and KCS as well as the presence of autoimmune antibodies and histopathological salivary gland involvement. Because of the lack of a "gold standard" for SS, the standard of reference being actually used is clinical diagnosis made by an experienced clinician. The lack of specific diagnostic tests combined with the high frequency of sicca symptoms in the general population makes the diagnosis of SS even more complicated. This holds true especially in early disease where the symptoms and signs are usually mild and might explain the time delay for the diagnosis of SS. The importance of making the diagnosis of pSS is cardinal because of the increased risk of developing lymphoma and serious systemic complications. In an endeavor to increase the likelihood of diagnosis of SS, newer diagnostic tools have been devised such as ultrasound sonography of salivary glands, magnetic

Even if tremendous progress in the field of research has been made to unveil the different mechanistic processes underlying the development of SS, the initial triggering events of the disease have yet to be unearthed. Central to the pathophysiology of SS is chronic perpetual stimulation of the autoimmune system. Both B and T cells are implicated in the pathogenesis of the SS, even though the mechanisms underlying humoral and cellular abnormalities are

resonance imaging of parotid glands as well as epigenetic biomarkers.

not yet known (Delaleu et al., 2008; Mariette & Gottenberg, 2010).

**2. Pathophysiology of Sjögren's syndrome**

**1. Introduction**

**of Sjögren's Syndrome**

*1Departments of Rheumatology*

*2Internal Medicine*

*Belgium*

Muhammad S. Soyfoo1 and Elie Cogan2

*Erasme Hospital, Université Libre de Bruxelles,*

### **Diagnostic and Prognostic Features of Sjögren's Syndrome**

Muhammad S. Soyfoo1 and Elie Cogan2

*1Departments of Rheumatology 2Internal Medicine Erasme Hospital, Université Libre de Bruxelles, Belgium*

#### **1. Introduction**

Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by the lymphocytic infiltration of salivary and lacrymal glands leading to xerostomia and keratoconjunctivitis sicca (KCS). The prevalence of SS is variable but recent studies have estimated it to be between 0.1-0.6%(Goransson et al., 2011; Trontzas & Andrianakos, 2005). As such, SS occurs in middleaged patients with a high female predominance of 9 to 1 (Fox, 2005). SS is classified either as primary (pSS) when occurring alone or secondary (sSS) to other autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus. Besides the involvement of exocrine glands entailing the classical sicca syndrome, systemic manifestations resulting from the lymphocytic infiltration of organs can be present in up to 20% of cases. There are actually no specific diagnostic criteria for SS, but for clinical studies and teaching purposes, SS is classified according to the American-European classification criteria, which include subjective and objective criteria of xerostomia and KCS as well as the presence of autoimmune antibodies and histopathological salivary gland involvement. Because of the lack of a "gold standard" for SS, the standard of reference being actually used is clinical diagnosis made by an experienced clinician. The lack of specific diagnostic tests combined with the high frequency of sicca symptoms in the general population makes the diagnosis of SS even more complicated. This holds true especially in early disease where the symptoms and signs are usually mild and might explain the time delay for the diagnosis of SS. The importance of making the diagnosis of pSS is cardinal because of the increased risk of developing lymphoma and serious systemic complications. In an endeavor to increase the likelihood of diagnosis of SS, newer diagnostic tools have been devised such as ultrasound sonography of salivary glands, magnetic resonance imaging of parotid glands as well as epigenetic biomarkers.

#### **2. Pathophysiology of Sjögren's syndrome**

Even if tremendous progress in the field of research has been made to unveil the different mechanistic processes underlying the development of SS, the initial triggering events of the disease have yet to be unearthed. Central to the pathophysiology of SS is chronic perpetual stimulation of the autoimmune system. Both B and T cells are implicated in the pathogenesis of the SS, even though the mechanisms underlying humoral and cellular abnormalities are not yet known (Delaleu et al., 2008; Mariette & Gottenberg, 2010).

Diagnostic and Prognostic Features of Sjögren's Syndrome 125

The most prominent clinical feature of SS is the sicca syndrome of xerostomia and keratoconjunctivitis sicca (KCS) resulting from lymphocytic infiltration of salivary and lachrymal glands. The sicca syndrome is often extended to other organs and might result in skin dryness, vaginal dryness resulting in dyspareunia, and respiratory tract dryness.

More than 90% of patients with SS complain of symptoms resulting from functional alteration of salivary glands. Patients often complain of unpleasant taste, difficulties in eating dry food, the need to drink more water or difficulties in controlling dentures. In the early stages of SS, the mouth may appear to be moist, but with disease progression, pooling of saliva in the floor of the mouth disappears, thereby unveiling the lines of contact between frothy saliva and oral soft tissue. With disease progression and especially in advanced stages of SS, the oral mucosa becomes extremely dry and tends to form wrinkles. The surface of the tongue becomes red and lobulated with partial or complete depapillation. The symptoms of xerostomia extend to a painful syndrome with the sensation of permanent burns, soreness, taste alteration, "clicking quality" in the speech of patients with SS, tongue fissuring, dysphagia and angular cheilitis. Gross accumulation of plaque might prevail. Infections by staphylococcus aureus or pneumococcus can result in acute sialadenitis. With further disease progression, teeth decay, periodontal infections, increased incidence of candidiasis infections and ultimately loss of teeth are possible complications (Fox, 2005,

Ocular dryness in SS, also known as keratoconjunctivitis sicca (KCS), is often less prominent than xerostomia. A detailed anamnestic investigation is necessary to detect ocular dryness symptoms. The main complaint of KCS is foreign-body sensation, but other symptoms such as grittiness, thick rope like secretions at the inner canthus, photosensitivity, burns, and sensation of having a veil before the eyes, absence of tears after irritation or emotion are all frequent features of KCS. Ocular dryness is due to the lymphocytic infiltration of lacrimal glands leading to diminished lacrimal flow and tear composition, thereby altering corneal and conjunctival epithelia, characterizing the known condition of keratoconjunctivitis sicca (KCS). In more severe disease, functional disability with visual impairment occurs. Complications of KCS include corneal ulcerations that can lead to perforations and

Approximately 70% of patients with SS complain of articular manifestations. The main articular features are predominantly arthralgia while arthritis is less frequent (Fauchais et al., 2010). Polyarthralgia is relapsing and remitting. Symmetric, non-erosive, polyarthritis

aberrant lymphocyte homing, T cell cytotoxicity, apoptosis and autoantibodies formation and further glandular destruction. BAFF: B-cell activating factor; Dc dendritic cells; IFN:

interferon; IL-1: interleukin-1; TNF-: tumor necrosis factor .

**3.1 Xerostomia**

Kassan & Moutsopoulos, 2004).

**3.2 Keratoconjunctivitis sicca**

iridocyclitis (Fox, 2005).

**3.3 Systemic manifestations**

**3.3.1 Musculoskeletal manifestations**