Methotrexate as an Alternative Therapy for Chronic Calcium Pyrophosphate Deposition Disease

ARTHRITIS & RHEUMATISM Vol. 56, No. 2, February 2007, pp 688 692 DOI 10.1002/art.22389 2007, American College of Rheumatology Methotrexate as an Alternative Therapy for Chronic Calcium Pyrophosphate Deposition Disease An Exploratory Analysis Amélie Chollet-Janin, 1 Axel Finckh, 1 Jean Dudler, 2 and Pierre-André Guerne 1 Objective. To evaluate the effectiveness of methotrexate (MTX), which works not only as an immunosuppressant, but also as a potent antiinflammatory agent, as an alternative therapeutic option for patients with severe calcium pyrophosphate deposition disease (CPDD) who fail to respond to standard therapy with nonsteroidal antiinflammatory drugs and/or glucocorticoids. Methods. We analyzed, in 2 university hospitals in Switzerland, consecutive patients with CPDD that was resistant to classic treatment and were subsequently treated with MTX. Before and after initiation of MTX therapy, we quantified the frequency of pseudogout attacks, pain intensity, the number of swollen and tender joints, and inflammatory biomarkers. Clinical and biologic side effects of MTX and patients satisfaction with MTX treatment were also evaluated. Results. The study included 5 patients treated with low dosages of MTX (5 20 mg/week). The mean followup time with MTX was 50.4 months (range 6 81 months). All patients reported an excellent clinical response, with marked within a mean period of 7.4 weeks. A significant decrease in pain intensity (P < 0.0001), swollen and tender joint counts (P < 0.0001), and frequency of attacks was observed. The biomarkers of inflammation decreased markedly Dr. Finckh s work was supported by a scholarship from the University of Geneva. 1 Amélie Chollet-Janin, MD, Axel Finckh, MD, MS, Pierre- André Guerne, MD, PD: University Hospital of Geneva, Geneva, Switzerland; 2 Jean Dudler, MD: University Hospital of Lausanne, Lausanne, Switzerland. Address correspondence and reprint requests to Pierre- André Guerne, MD, PD, University Hospital of Geneva, Division of Rheumatology, 26 Avenue de Beau-Séjour, 1211 Geneva 14, Switzerland. E-mail: pierre-andre.guerne@hcuge.ch. Submitted for publication June 20, 2006; accepted in revised form October 30, 2006. when systematically analyzed (3 patients). No significant side effects were reported. Conclusion. This study suggests that MTX could be a valuable therapeutic option for severe CPDD that is refractory to conventional therapy. Chondrocalcinosis, or calcium pyrophosphate deposition disease (CPDD), is a common and potentially severe metabolic arthropathy caused by calcium pyrophosphate dihydrate (CPPD) crystal deposition (1). CPDD is particularly frequent in the half of life, with radiographic evidence in up to 5% of the human population and with the prevalence rising almost linearly to 15% over 60 years of age and 30 40% in those over 80 years of age (2). Although frequently asymptomatic, CPDD can cause severe acute attacks of inflammatory arthritis (pseudogout), mainly in the knees and wrists, as well as various forms of chronic, frequently destructive, arthropathies. CPDD can be divided into 3 main subtypes: a widespread but paucisymptomatic form resembling osteoarthritis, a type of rapidly destructive arthropathy, and a highly inflammatory chronic arthropathy that mimics rheumatoid arthritis (RA). The pathogenesis of inflammation due to CPDD is related to the recruitment, activation, and proliferation of numerous cells, including polymorphonuclear neutrophils (PMNs), and the synthesis, expression, and secretion of abundant mediators of inflammation and/or catabolic enzymes. CPPD crystals have direct catabolic effects on cartilage and synovium, and thus, do not require inflammation for catabolism (1,3,4). No currently available drug is known to prevent the progression of CPPD crystal deposition and gradual joint deterioration. Treatment is therefore essentially symptomatic. Nonsteroidal antiinflammatory drugs (NSAIDs) and intraarticular or systemic glucocorticoids are the main 688

MTX AS ALTERNATIVE THERAPY IN CPPDD 689 Table 1. Patient/ age/sex Patient demographic characteristics and treatments* Chondrocalcinosis, primary or ary Disease duration, years Medications taken prior to MTX initiation MTX dosage Folic acid dosage 1/54/M Primary 1 NSAIDs, prednisone 15 mg/week SC 10 mg/week 2/69/F Secondary 12 NSAIDs, prednisone, intraarticular 12.5 mg/week orally 10 mg/week (hyperparathyroidism) glucocorticoids 3/74/F Primary 15 NSAIDs, prednisone 15 mg/week orally 10 mg/week 4/90/F Primary 30 NSAIDs, prednisone, colchicine 10 mg/week SC 15 mg/week 5/66/F Primary 12 Intramuscular glucocorticoids 5 20 mg/week orally 15 mg/week * MTX methotrexate; NSAIDs nonsteroidal antiinflammatory drugs; SC subcutaneously. therapies for CPDD disease, and colchicine can be useful in selected patients with recurrent attacks of pseudogout (5). However, treatment often remains unsatisfactory and unable to prevent disease progression. Methotrexate (MTX) has been shown to display various antiinflammatory effects, including downregulation of PMN recruitment and activation. We therefore used this drug in 5 patients with severe CPDD who had failed to respond to standard therapy, and we analyzed the clinical and biologic outcomes. PATIENTS AND METHODS We studied all consecutive patients with severe recurrent attacks of pseudogout and/or chronic CPDD treated with MTX between August 1998 and October 2005 in the rheumatology units of the university hospitals of Geneva and Lausanne. We retrospectively assessed the frequency of pseudogout attacks, pain intensity (using a 10-cm visual analog scale, where 0 no pain and 10 extreme pain), number of swollen and tender joints, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level before and after MTX initiation, based on patients charts and on patients and physicians retrospective appraisals. An evaluation was performed from a mean of 2 4 visits starting 4 6 weeks after MTX initiation. Clinical and biologic side effects of MTX and patient satisfaction with MTX treatment were evaluated in the same manner. All patients fulfilled the diagnostic criteria for CPDD proposed by McCarty (CPPD crystals shown in tissues or synovial fluid by compensated polarized light microscopy and typical calcifications present on radiographs) (6). None of these patients had clinical, biologic, or radiologic signs consistent with conditions known to respond to MTX, such as RA, polymyalgia rheumatica, or psoriatic arthritis; in particular, none had nodules, skin psoriasis, rheumatoid factors, anti citrullinated peptides, or erosions consistent with RA. Previous medications taken by these patients had included, when indicated or possible, NSAIDs, intraarticular and/or systemic steroids, and colchicine (Table 1). Since all had failed to respond to standard therapy, MTX was introduced as an alternative therapeutic option. The evolution of clinical and biologic outcomes after MTX initiation was analyzed using a longitudinal regression model of repeated measures (trend test). In addition, we examined the percent reduction of these outcomes at the next available visits by dividing the difference between visits by the baseline value. Two-sided P values less than or equal to 0.05 were considered statistically significant. RESULTS All 5 study patients were white and were followed up in the university hospitals of Geneva and Lausanne for a mean period of 6.2 years (range 1 11 years). The mean age at disease onset was 70.6 years, and the mean disease duration was 14 years. The median MTX dosage was 12.5 mg/week, administered orally or subcutaneously (Table 1). All patients received concomitant folic acid supplementation at a mean dosage of 12 mg/week. The mean followup time with MTX was 50.4 months (range 6 81 months). At baseline, the patients had arthralgias for a median of 10 days per month (interquartile range [IQR] 2 31), a median of 5 swollen joints (IQR 4 8), and a median of 11 tender joints (IQR 10 11). In all 5 patients, pain intensity decreased significantly (P for trend 0.0001) after starting MTX. The number of days during which patients had arthralgias also significantly decreased (P for trend 0.05), as did the number of swollen joints (P for trend 0.0001) and tender joints (P for trend 0.0001). At the first visit following MTX initiation, the median reduction in pain intensity was 62.5% (IQR 38 64%), with a 60% reduction (IQR 51 61%) in the number of days with arthralgias, 75% reduction (IQR 50 80%) in the number of swollen joints, and 70% reduction (IQR 53 81%) in the number of tender joints. The mean time before was observed was 7.4 weeks (range 4 16 weeks) (Table 2).

690 CHOLLET-JANIN ET AL Table 2. Outcome of methotrexate (MTX) therapy in patients with calcium pyrophosphate deposition disease Patient Pain intensity score Episode frequency Number of swollen joints Number of tender joints Patient s subjective satisfaction with MTX treatment MTX interruption/ resumption Approximate time before Side effects 1 7/2 Persistent/1 per month 2 6 8/2 3 4 5 per year/ 1 2 per year 3 8 10/5 6 3 4 per year/ 2 3 per year 4 8/3 Persistent/1 per week 5 6/4 2 3 per week/ 1 per week 5/1 11/2 Miraculous Not attempted 4 6 weeks None 8/2 10/3 Very satisfied Increase in symptoms/ 8/0 8 17/0 17 Felt much better but with a transient effect Increase in symptoms/ 4/2 11/7 9 Very satisfied Increase in symptoms with half-dose of MTX or switch to oral prescription/ 4 6 weeks/ 4 weeks the time 4 6 weeks/ 3 weeks the time None 8 weeks None Transient lymphopenia (0.46 10 9 /liter); spontaneous resolution, without MTX interruption or dosage decrease 4/0 1 7/0 2 Satisfied Not attempted 3 4 months Stomatitis (resolved with folic acid) * Pain intensity was assessed using a 0 10-cm visual analog scale, where 0 no pain and 10 extreme pain.

MTX AS ALTERNATIVE THERAPY IN CPPDD 691 Two patients tried to stop taking MTX, since they were convinced of disease remission and were hoping that they could do without the drug. In those 2 cases, arthralgias and/or arthritis progressively recurred, and resumption of MTX was followed by again 4 weeks later. All 5 patients expressed at least satisfaction to great satisfaction with MTX treatment, and 1 of them even qualified it as a miraculous drug (Table 2). These clinical effects correlated with in the ESR and CRP levels, when analyzed (results are missing in 2 patients). In patients 1, 4, and 5, the ESR decreased from 80 to 6 mm/hour, 34 to 14 mm/ hour, and 25 to 13 mm/hour, respectively, and CRP levels decreased from 50 to 5 mg/dl, 11 to 1 mg/dl, and 40 mg/dl to undetectable, respectively. No significant side effects were reported. One patient had transient stomatitis, which completely resolved with folic acid supplementation. Another patient had transient lymphopenia (0.46 10 9 /liter), which resolved without MTX interruption or decrease in the dosage (Table 2). DISCUSSION We hypothesized that MTX could represent a good therapeutic option in CPDD, particularly for patients in whom classic treatments are not tolerated and/or are ineffective. The results suggest that low-dose MTX diminishes the severity of chronic CPDD by decreasing the frequency of pseudogout attacks, pain intensity, and the number of swollen and tender joints. When examined, the ESR and CRP levels were also seen to decrease markedly. Although impressive, the latter data must be considered with caution since they only represent single assessments before and after MTX initiation. MTX is an immunosuppressive agent commonly used in numerous immunoinflammatory conditions, including RA and psoriatic arthritis, but generally not in purely inflammatory diseases. Several studies have demonstrated that CPPD crystals can induce activation of endothelial cells, fibroblasts, synoviocytes, and chondrocytes, as well as the recruitment and degranulation of PMNs. This unlocks a cascade of inflammatory processes, with abundant production and release of cytokines (including interleukin-1 [IL-1], IL-6, and IL-8), reactive oxygen species, and catabolic enzymes (1,4). These molecules are eventually responsible for subsequent articular damage (3,7). Since no treatment is presently known to prevent the deposition of CPPD crystals in cartilage, the goals of current therapies are therefore to control inflammation and, hopefully, prevent or slow eventual destruction. Commonly used drugs include NSAIDs, glucocorticoids, and colchicine, but many patients fail to respond adequately to these, which calls for new therapeutic alternatives. MTX was first known as a specific antagonist of folic acid with cytostatic effects on malignant cells, similar to the inhibition of dihydrofolate reductase (DHFR), with consequent suppression of purine and pyrimidine synthesis. The mechanisms of action of MTX, however, recently proved much more complex, with well-demonstrated immunosuppressive and antiinflammatory effects. Regarding its antiinflammatory effects, MTX also inhibits the accumulation of polyamines (8) by blocking DHFR; these toxic compounds can contribute to tissue injury in inflamed joints. Most of the antiinflammatory actions of MTX, however, appear to be related to the promotion of the release of adenosine (9). This potent endogenous antiinflammatory mediator diminishes PMN adhesion, inhibits the generation of superoxide anions by stimulated monocytes, and modulates cytokine production. Concerning this, MTX was shown to decrease the synthesis of IL-1, one of the most potent proinflammatory and catabolic cytokines, and increase the synthesis and release of the IL-1 receptor antagonist (10). These anti IL-1 effects have the potential to slow and possibly prevent joint deterioration in conditions such as CPDD. At low dosages ( 15 25 mg/week), MTX is supposed to act primarily as an antiinflammatory drug, rather than as an antiproliferative agent (8). Numerous studies of RA have shown a strong, rapid, and sustained response, with a preventive effect on radiographic progression (11). MTX might therefore slow or prevent destructive changes in CPDD as well. MTX at low doses is generally well tolerated and appears to be among the safest treatments for RA, if well monitored (8,12 14). Furthermore, MTX is economical, with a particularly favorable cost:effectiveness ratio (15). The current financial constraints of most health systems and the growing incidence of CPDD in an aging population make MTX a particularly worthwhile therapeutic alternative. This is, to the best of our knowledge, the first report of beneficial effects of MTX in CPDD. The value of this observation is obviously limited by the small number of subjects, the retrospective evaluation, and the absence of a control group. The cyclic nature of CPDD could further bias these results. However, the extent and consistency of the observed effects, together with the fact that flares quickly followed treatment interruptions

692 CHOLLET-JANIN ET AL or dosage decreases, strongly suggest that MTX caused a real and substantial. Further studies, particularly a prospective randomized trial, are definitely needed to confirm these findings and to define the place of MTX in the management of CPDD. It is important to point out that, although relatively safe in elderly patients (12), MTX can be toxic in this age group, particularly in the presence of renal impairment. Its use in the treatment of CPDD would obviously imply careful individual evaluation of the risk:benefit ratio and close monitoring of potential side effects. In conclusion, our observations suggest that MTX could be a valuable therapeutic option for severe CPDD refractory to conventional therapy. The antiinflammatory effects of MTX represent a plausible mechanism for its beneficial effects. AUTHOR CONTRIBUTIONS Dr. Chollet-Janin had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study design. Drs. Chollet-Janin, Finckh, and Guerne. Acquisition of data. Drs. Chollet-Janin, Dudler, and Guerne. Analysis and interpretation of data. Drs. Chollet-Janin, Finckh, and Guerne. Manuscript preparation. Drs. Chollet-Janin, Finckh, Dudler, and Guerne. Statistical analysis. Drs. Chollet-Janin and Finckh. REFERENCES 1. Johnson K, Terkeltaub R. Inorganic pyrophosphate (PP I ) in pathologic calcification of articular cartilage [review]. Front Biosci 2005;10:988 97. 2. Zhang Y, Brown MA. Genetic studies of chondrocalcinosis [review]. Curr Opin Rheumatol 2005;17:330 5. 3. Dalbeth N, Haskard DO. Inflammation and tissue damage in crystal deposition diseases. Curr Opin Rheumatol 2005;17:314 8. 4. Cheung HS. Calcium crystal effects on the cells of the joint: implications for pathogenesis of disease. Curr Opin Rheumatol 2000;12:223 7. 5. Alvarellos A, Spilberg I. Colchicine prophylaxis in pseudogout. J Rheumatol 1986;13:804 5. 6. McCarty DJ. Calcium pyrophosphate dihydrate crystal deposition disease: nomenclature and diagnostic criteria. Ann Intern Med 1977;87:241 2. 7. Cheung HS. Biologic effects of calcium-containing crystals [review]. Curr Opin Rheumatol 2005;17:336 40. 8. Cronstein BN. Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev 2005;57:163 72. 9. Hasko G, Cronstein BN. Adenosine: an endogenous regulator of innate immunity [review]. Trends Immunol 2004;25:33 9. 10. Seitz M. Molecular and cellular effects of methotrexate [review]. Curr Opin Rheumatol 1999;11:226 32. 11. Weinblatt ME, Polisson R, Blotner SD, Sosman JL, Aliabandi P, Baker N, et al. The effects of drug therapy on radiographic progression of rheumatoid arthritis: results of a 36-week randomized trial comparing methotrexate and auranofin [published erratum appears in Arthritis Rheum 1993;36:1028]. Arthritis Rheum 1993;36:613 9. 12. Hirshberg B, Muszkat M, Schlesinger O, Rubinow A. Safety of low dose methotrexate in elderly patients with rheumatoid arthritis. Postgrad Med J 2000;76:787 9. 13. Weinblatt ME, Maier AL, Fraser PA, Coblyn JS. Longterm prospective study of methotrexate in rheumatoid arthritis: conclusion after 132 months of therapy. J Rheumatol 1998;25:238 42. 14. Yazici Y, Sokka T, Kautiainen H, Swearingen C, Kulman I, Pincus T. Long term safety of methotrexate in routine clinical care: discontinuation is unusual and rarely the result of laboratory abnormalities. Ann Rheum Dis 2005;64:207 11. 15. Choi HK, Seeger JD, Kuntz KM. A cost effectiveness analysis of treatment options for methotrexate-naive rheumatoid arthritis. J Rheumatol 2002;29:1156 65.