Ivan Padjen

Clinical Implications for Cannabinoid Use in the Rheumatic Diseases Potential for Help or Harm

Cannabinoids as therapeutic agents in traditional medicine are both lauded and maligned. The ubiquitous use in years gone by once made cannabinoids a mainstay of the physician’s dispensary, yet the understanding of the pharmacology of these drugs is relatively recent. The physiologic and psychoactive effects of the cannabis, or hemp, plant, cultivated in ancient times for the production of textiles, led to ceremonial, therapeutic, and eventual recreational use, beginning in the Himalayan region of central Asia and with the first recorded medicinal use in China in 2700 BC (1). In the Western world, 2 paths of scientific study of cannabinoids have been followed. In the earliest studies, 19th century French psychiatrists focused on the effects on mood, whereas British physicians explored the sedative, analgesic, hypnotic, and anticonvulsive properties (1). In the early 20th century, interest in cannabis as a therapeutic agent waned following the introduction of drugs with a more reliable therapeutic profile, such as opiates. With increasing global concerns about narcotic addiction, cannabis was misclassified as a narcotic, similar to heroin, opium, and cocaine, at the Geneva International Convention on Narcotics Control in 1925, which resulted in a ban on cannabis for recreational use in the UK in 1928 and criminalization in the US in 1937 (1,2). Renewed interest in the therapeutic effects of cannabinoids emerged following the identification and cloning of cannabinoid receptors in the late 1980s and 1990 (3–5). The endocannabinoid system, found throughout the animal kingdom, comprises endogenous ligands, termed endocannabinoids, and receptors. This system has effects on pain mechanisms, immune function, inflammation, and bone health, as has been noted in the laboratory setting. However, formal clinical study has been limited. Therefore, the true efficacy and risk/ benefit ratio with regard to the therapeutic effects of cannabinoids, whether derived from the hemp plant Cannabis sativa or synthesized from cannabis derivatives, remain controversial (6). The use of cannabinoids as therapeutic agents has mostly remained outside mainstream medicine in modern times and is further prejudiced by the recreational use of marijuana, a drug associated with abuse with a reported usage rate of 4% of the global population (2,3). Because more than 60 alkaloids are present in the plant form, and because there has been increasing identification of endocannabiMary-Ann Fitzcharles, MB, ChB, FRCPC: McGill University Health Center and McGill University, Montreal, Quebec, Canada; Jason McDougall, PhD: Dalhousie University, Halifax, Nova Scotia, Canada; Peter A. Ste-Marie, BA: McGill University Health Center and University of Montreal, Montreal, Quebec, Canada; Ivan Padjen, MD: University Hospital Centre Zagreb and University of Zagreb, Zagreb, Croatia. Dr. Fitzcharles has received consulting fees, speaking fees, and/or honoraria from Eli Lilly, Janssen, Pfizer, and Purdue Pharma (less than

Redefining a diagnosis: from meningeal plasma cell granuloma to rheumatoid meningitis. Report of a patient follow-up

10,000 each) and has provided expert testimony regarding pain related to rheumatic conditions for the plaintiff and the defense in court trials. Dr. McDougall has received consulting fees from Eli Lilly (less than

The lobster sign in SAPHO syndrome: unusually extensive osteitis of the anterior chest wall partially responsive to infliximab

10,000). Address correspondence to Mary-Ann Fitzcharles, MB, ChB, FRCPC, Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada. E-mail: mary-ann.fitzcharles@ muhc.mcgill.ca. Submitted for publication December 27, 2011; accepted in revised form April 24, 2012. Arthritis & Rheumatism

AB0460 Causes of Early and Late Death of Patients with Systemic Lupus Erythematosus over A 10-Year Period

Sir, In one of the previous issues of your Journal, we presented a patient with non-infectious meningitis, histologically characterized as plasma cell granuloma [1]. During the further months of follow-up, the patient developed mild normocytic anemia and a moderately elevated level of C reactive protein (CRP, 43.3 mg/l, normal values\5.0 mg/l) with unequivocally elevated levels of the rheumatoid factor (RF, 171.7 IU/ml, normal values \15.0 IU/ml) and antibodies against cyclic citrullinated peptides (anti-CCP, 405.3 IU/ml, normal values\7.0 IU/ ml). Although she was initially without signs and symptoms of arthritis, during the following weeks after obtaining these laboratory results the patient developed gradually worsening pain, swelling and morning stiffness of several joints, including both radiocarpal joints, the right elbow, right knee, as well as bilateral talocrural joints (Fig. 1). The clinical presentation consistent with polyarthritis in addition to elevated CRP levels and pronouncedly increased levels of RF and anti-CCP were sufficient for the diagnosis of rheumatoid arthritis. The patient was started on a regimen of a gradually tapered daily dose of methylprednisolone in addition to weekly methotrexate. Treatment led to stable remission of arthritis and further regression of the previously noted neurological deficit. The clinical course of the patient’s disease was followed by the development of our understanding of the clinical context in which the meningeal lesions took place. Although we previously concluded that the plasma cell granulomatous meningitis in our patient was an isolated finding and a primary disease of the meninges, the further disease course warranted a redefinition of the patient’s diagnosis, making rheumatoid arthritis the primary disease and (rheumatoid) meningitis its central nervous system manifestation. Rheumatoid meningitis (RM) is an extremely rare manifestation of rheumatoid arthritis (RA). The largest case series ofRM [2] involved 19 patients,most ofwhichwere diagnosed with RM post mortem based on autopsy findings (17 of 19 patients). That would probably not be the case nowadays, given the availability and development of sophisticated imaging methods, primarily magnetic resonance imaging. Patients from the case series [2] developed RM late in course of RA (after amedian of 14 years following diagnosis of RA). This makes the occurrence of RM as the initial disease manifestation evenmore unusual, although it was described in the literature in the recent years [3]. Both the leptoand the pachymeninges may be affected in patients with rheumatoid meningitis [2]. It is interesting tomention that the neurological manifestations observed in our patient (predominantly including seizures and paresis) are considered to be consistent with leptomeningitis, while symptoms such as headache and cranial neuropathies are ascribed to pachymeningitis [4]. Despite the unquestionable utility of imaging methods and I. Padjen (&) M. Mayer Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, University Hospital Centre Zagreb, Kispaticeva 12, Zagreb, Croatia e-mail: ivan_padjen@yahoo.ca

AB0508 Frequency of the American College of Rheumatology (ACR) Classification Criteria in A Group of Patients with Systemic Lupus Erythematosus (SLE) Deceased during A 6-Year Period

The synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is an uncommon entity comprising several osteoarticular and cutaneous features [1]. Osteitis and hyperostosis remain key diagnostic features, since the proposed clinical criteria [2] have never been validated, especially regarding the distinction between the SAPHO syndrome and psoriatic arthritis [3]. Tumor necrosis factoralpha (TNF-a) antagonists are starting to play an important role in the treatment of patients inadequately responsive to conventional treatment [4]. We present a 48-year-old female patient diagnosed with SAPHO syndrome 5 years ago. She has been treated with nonsteroidal anti-rheumatics, sulfasalazine and methylprednisolone, with partial and unsatisfactory response in terms of clinical and laboratory features, as well as radiological and bone scan findings [5, 6]. Four years after initiating conventional treatment, she underwent a reevaluation to assess disease extent and activity. Physical examination revealed palmoplantar pustulosis and multiple joint tenderness, including sternoclavicular, costochondral, sacroiliac and peripheral joints. Laboratory investigation revealed elevated inflammatory markers, also suggesting disease activity. A technetium 99-m bone scan was subsequently performed [5]. Increased tracer uptake was observed in both sternoclavicular joints, the sternum, first ribs bilaterally, fifth and sixth ribs near the costosternal junctions and the anterior portion of the eighth left rib, resembling a lobster. It was also revealed in the right hip and pubic bone, as well as in the pubic symphysis (Fig. 1). Less pronounced accumulation was noticed in the L4 and L5 vertebrae. Infliximab was added to the treatment, leading to an almost complete regression of osteoarticular complaints and normalization of laboratory findings. However, a follow-up bone scan performed after the fourth application of infliximab revealed a pattern of tracer accumulation almost identical to the one described previously. Moreover, psoriasiform skin lesions developed on the palms and trunk following the introduction of the biological agent: although similar lesions were observed before, they were now more pronounced. The skin lesions disappeared within several weeks following the fifth application of infliximab. TNF-a antagonists are included in standard treatment strategies for seronegative spondyloarthropathies; however, their use in the SAPHO syndrome is still considered as off-label [4]. This might change in the future due to new insights into their role on the molecular level [7] and an increasing number of individual reports suggesting a positive impact on disease activity [4]. Nevertheless, some questions still remain to be answered. Our patient experienced a temporary aggravation of cutaneous lesions, which is in accordance with other authors’ findings [8]. The aggravation is probably a side effect of infliximab and not a result of worsening of the disease course. Furthermore, the impact of infliximab on bone tracer uptake should also be addressed. Although an alleviation of osteoarticular complaints was observed soon after the beginning of the biological treatment, no regression was observed on the control B. Anić I. Padjen (&) M. Barešić Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, University of Zagreb School of Medicine, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia e-mail: ivan_padjen@yahoo.ca

Clinical Features of the SAPHO Syndrome and their Role in Choosing the Therapeutic Approach: Report of Four Patients and Review of the Literature

Background Causes of death (CODs) of patients with systemic lupus erythematosus (SLE) comprise active SLE and comorbidities that develop as a result of SLE and immunosuppressive therapy: infections, cardiovascular disease and malignant tumors. Active disease and infections are typical causes of early death, while cardiovascular disease typically causes late death. However, COD frequencies depend on the source population and data ascertainment method. Objectives To identify and compare causes of early and late death of SLE patients deceased during a ten-year period. Methods We retrospectively identified SLE patients followed-up by our Department, deceased between 2002 and 2011, and included patients with ≥4 classification criteria of the American College of Rheumatology (ACR), ≥18 years of age and Croatian residency at the time of death. Death and causes of death were retrospectively identified using patient medical records, as well as death certificates and autopsy reports, when available. We also matched data on all SLE patients that visited our Department from 2002 to 2011 with the National Mortality Database. We classified CODs into five categories: active SLE, cardiovascular disease, infection, malignant tumor and other. More than one COD category was possible in a single patient. We compared the frequencies of each COD category between patients deceased within and after 5 years following diagnosis (early vs. late death). Frequencies were compared using the χ2 and Fishers exact test, and continuous variables using the t-test and Mann-Whitney U test. The study was approved by the local ethics committee. Results We identified 90 deceased patients (68 females, 22 males; 21 in the early death group (EDG), 69 in the late death group (LDG)). EDG patients were older than LDG patients at diagnosis (mean age±SD: 56±15 vs. 46±17 years; p=0.005), but there was no difference between the age at death (mean age±SD: 58±15 years for all patients). Patients were followed-up for a median of 10 years (IQR: 5–15 years). LDG patients fulfilled a higher number of ACR criteria compared to EDG patients (median, IQR: 6, 5–7 vs. 5, 4–6; p=0.018). No difference between COD category frequencies was detected between EDG and LDG. Nevertheless, infections and active SLE were leading causes of early death (9/21 and 8/21, respectively), while cardiovascular disease was the most frequent cause of late death (30/69), followed by infection and active SLE (21/69 and 18/69, respectively)(Table). SLE was mentioned in the death-related medical records of only 41/90 patients. Cause of death Patients deceased % Early death Late death (N=90) (N=21) (N=69) Active disease (SLE) 26 29 8 18 Infection 30 33 9 21  a) Sepsis 20 22 6 14  b) Pneumonia 18 20 5 13  c) Urinary tract infection 8 9 3 5 Cardiovascular disease 36 40 6 30  a) Myocardial infarction + ischemic heart disease 12 (7+5) 13 1 11  b) Myocardial infarction 5 6 1 4  c) Stroke 8 9 0 8  d) Pulmonary embolism 3 3 1 2 Malignant tumor 15 17 1 14 Other 10 11 4 6 Unknown 8 9 1 7 Conclusions Infections and active SLE are leading causes of early death, while cardiovascular disease is the most frequent cause of late death in SLE. Lack of recording of SLE in death-related medical records requires matching of clinical data with a complementary source, such as a population-based mortality database, to identify deceased SLE patients. References Nossent J et al. Lupus 2007;16:309–17. Disclosure of Interest None declared

Drugs Used in Rheumatic Disease

Background Although the number of fulfilled ACR criteria is not a feature of disease severity in patients with systemic lupus erythematosus (SLE), renal and neurologic involvement are associated with a severe disease course (1,2). Objectives Comparison of the number of fulfilled ACR criteria between SLE patients (a) deceased early and late during the disease course and (b) identified and not identified as deceased in the period from 2006 to 2011. Methods Data were retrieved from our hospital-based registry of SLE patients. Patients with a clinical diagnosis of SLE and at least one visit to the Centre in the 2006-2011 period or death in the same period were analyzed. Deceased patients were identified using the registry and death certificates. The number of fulfilled ACR criteria was counted for each patient. The χ2 test and Fisher exact test, as well as the Student t-test were used to evaluate differences between categorical and continuous variables, respectively. The study was approved by the hospital ethics committee. Results The total number of SLE patients with at least one visit to the Centre between 2006 and 2011 identified from the registry was 702. The frequency of ACR criteria was available for 693/702 patients. We identified 48 deceased patients (31 females and 17 males): 28 using the registry and 20 using death certificates - the latter were lost to follow-up before 2006. Data on the year of diagnosis and fulfillment of ACR criteria were not available for 4 deceased patients. The length of follow-up in the observed group of deceased patients was 12.09±7.38 years. Only 9/44 patients died within the first 5 years following diagnosis (early death). The rest of observed patients (35/44) died later during the disease course. The number of fulfilled criteria in the early and late death group was 4.11±1.05 and 4.71±1.56, respectively (difference not statistically significant). No difference was observed between the fulfillment of each of the criteria, except for the malar rash (19/35 in the late death group vs. 1/9 in the early death group, p=0.027). The frequency of renal disorder and discoid rash was significantly higher in the deceased patient group compared to patients not identified as deceased (21/44 vs. 167/665, χ2=9.702, p=0.002 and 20/44 vs. 128/665, χ2=15.610, p<0.001). No difference in frequencies of other criteria was observed between these two groups. Conclusions Renal disorder and discoid rash are more frequent among deceased SLE patients compared to patients not identified as deceased in the observed group. References Mak A, Cheung MW, Chiew HJ, Liu Y, Ho RC. Global trend of survival and damage of systemic lupus erythematosus: meta-analysis and meta-regression of observational studies from the 1950s to 2000s. Semin Arthritis Rheum. 2012;41:830-9. Doria A, Iaccarino L, Ghirardello A, Zampieri S, Arienti S, Sarzi-Puttini P, Atzeni F, Piccoli A, Todesco S. Long-term prognosis and causes of death in systemic lupus erythematosus. Am J Med. 2006;119:700-6. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3838