Abstract
Calcific periarthritis or calcific tendinitis occurs most frequently in the shoulder and rarely in the elbow. Cimetidine was previously reported to be effective for chronic calcific periarthritis of the shoulder. Here, we present five patients with chronic calcific periarthritis of the elbow treated by administration of cimetidine; there were six affected elbows in these five patients. Although all patients had been treated with nonsteroidal anti-inflammatory drugs for at least 3 months, their symptoms were not relieved. All patients took oral administration of cimetidine 400 mg daily. The pain was completely relieved in an average of 1.8 months after the administration of cimetidine, and the calcification of the elbow disappeared in an average of 5.1 months. During the follow-up period, there were no symptoms suggesting a recurrence. Although the detailed mechanism of action of cimetidine on periarticular calcifications remains to be understood, cimetidine appears to be a potential therapeutic agent for chronic calcific periarthritis.
Introduction
Calcific periarthritis or calcific tendinitis occurs most frequently in the shoulder and sometimes in other joints such as the hip, knee, wrist, and finger joints. 1 –4 The incidence of calcific periarthritis of the shoulder was reported to be 2.7% in the adult population. 5 Meanwhile, calcific periarthritis of the elbow is relatively rare. 6 Sandström reported that only 6 of 329 cases of calcific periarthritis occurred in the elbow. 7 Less familiarity with this condition involving a joint other than the shoulder could lead to a misdiagnosis or delay the definitive diagnosis. A previous report showed that only 1 of 12 patients with calcific periarthritis in joints other than the shoulder had an accurate preoperative clinical diagnosis. 8 The treatment of patients with calcific periarthritis is usually conservative, including nonsteroidal anti-inflammatory drugs (NSAIDs), rest, immobilization of the affected joint, therapeutic exercise, and local steroid injections. When conservative therapy does not work, needle aspiration, shock-wave therapy, and surgical treatment should be considered. Although the pathogenesis of calcific periarthritis is still unknown, oral administration of cimetidine was reported to be effective for chronic calcific periarthritis of the shoulder joint. 9 However, the detailed mechanism of action of cimetidine on calcific periarthritis is yet to be understood, and the effectiveness of cimetidine for chronic calcific periarthritis involving joints other than the shoulder has not been reported. Here, we present five patients with chronic calcific periarthritis of the elbow treated by administration of cimetidine.
Case report
Between 2012 and 2016, a total of 49 patients with refractory symptoms of periarthritis of the elbow were referred to our institute: six elbows in five patients (two males and three females) had radiographically verified calcific periarthritis. Although all five patients were treated with NSAIDs for at least 3 months, their symptoms were not relieved. Three of the five patients had a history of local steroid injections. The average age at the time of initiation of cimetidine administration was 50 years (range: 37–67 years). The average duration from the onset of symptoms to the administration of cimetidine was 34 months (range: 6–60 months). All patients provided written informed consent and started oral administration of cimetidine 400 mg daily (200 mg twice a day) combined with NSAIDs. No patients in this case series took other anti-reflux or anti-esophagitis medications at the time of presentation. We continued to prescribe cimetidine for 3 months, and we evaluated the change in the calcification on the radiographs once a month. If we could find any improvement in the pain or a decrease in the calcifications on radiographs within 3 months, we continued to prescribe cimetidine until the calcifications of the elbow totally disappeared.
The clinical features of all five patients are summarized in Table 1. Case 5 was the only patient with chronic calcific periarthritis of both elbows. The sites of the calcifications were medial epicondyle (three elbows) and lateral epicondyle (three elbows). The average size of the calcium deposits calculated on an anteroposterior (A-P) radiograph was 30 mm2 (range: 9.0–66 mm2) at the time of starting cimetidine therapy. In all five cases, the elbow pain was relieved within 3 months after initiation of orally administered cimetidine. No patient needed further treatment including surgical excision. After the initiation of cimetidine therapy, all patients experienced pain relief within 1 month. The pain was completely relieved in an average of 1.8 months (range: 1–3 months), and the calcification of the elbow disappeared after an average of 5.1 months (range: 2–9 months). During the follow-up period (average: 18 months), there were no symptoms suggestive of the recurrence of calcific periarthritis of the elbow.
Summary of clinical findings of the five cases.
F: female; M: male; R: right; L: left; Med.: medial; Lat.: lateral.
Representative case (case 4): A 44-year-old woman presented with a 6-month history of a painful nodule on her left elbow. She had been treated with oral NSAIDs for 3 months, but the symptoms were not changed and gradually worsened. Radiographs and magnetic resonance images of her left elbow showed calcifications outside the joint, suggesting chronic calcific periarthritis of the elbow (Figure 1). She desired surgical intervention because the pain became severe. We prescribed cimetidine 400 mg daily while the patient awaited surgery. One month later, her symptoms improved remarkably, and the radiographs showed decreased calcification. Two months after initiation of cimetidine, the pain was completely relieved, and the calcification was diminished on the radiographs (Figure 2).
(a) Initial radiographs taken at our facility. The calcification was identified in the lateral portion outside the elbow joint. MRI coronal (b) T1-weighted image and (c) T2-weighted fat-suppressed image. MRI showed the calcification was located outside the elbow joint with inflammatory changes in the surrounding soft tissues. MRI: magnetic resonance image.
(a) The radiograph after 1 month of cimetidine administration demonstrated reduction in the amount of the calcification. (b) The calcification completely disappeared after 2 months of cimetidine administration.
Discussion
Calcific periarthritis is usually monoarticular and commonly affects the shoulder. The calcium deposits are located in the soft tissues, such as tendons, tendinous tissues, ligaments, articular capsules, and their surrounding connective tissues. 7 According to Sandström, the clinical picture and the course of the calcific periarthritis were divided into acute, chronic, and latent forms. 7 In acute cases, characteristic symptoms are acute pain, local swelling, tenderness, restricted motility, and sometimes fever. Calcium deposits were seen on the radiographs and were finally absorbed spontaneously. McCarthy et al. reported that one-third of the patients with acute calcific periarthritis had an antecedent traumatic episode. 10 Compared to the acute form, the chronic form presents with less inflammatory findings and more insignificant symptoms, such as pain with motion and local tenderness. Our patients were considered to have the chronic form since they did not present with acute inflammation and they had a relatively long history of disease.
Calcific periarthritis is a cell-mediated disease in which metaplastic transformation into chondrocytes induces subsequent calcification. 11 Although the pathogenesis and dynamics of the calcification remain unclear, several etiological theories were previously suggested, such as ischemia, 12 degeneration, 13 and involvement of other factors (e.g. anti-inflammatory agents, metabolic disorders, and genetic predisposition). 14
Cimetidine is a histamine H2-receptor antagonist. Sherwood reported that patients with hyperparathyroidism became asymptomatic, normocalcemic, and normophosphatemic, with a normal level of parathyroid hormone (PTH) during treatment with cimetidine. 15 Jacob et al. evaluated the effects of cimetidine on circulating levels of immunoreactive PTH (iPTH), ionized calcium, magnesium, and phosphorus in patients on maintenance hemodialysis. 16 They found that cimetidine lowered iPTH levels without affecting serum concentrations of calcium, phosphorus, or magnesium. Thus, although the precise mechanism is still unknown, cimetidine is supposed to act on PTH and promote absorption of calcium deposits. Furthermore, Wakabayashi et al. reported that cimetidine combined with etidronate led to a marked improvement in both the subcutaneous and muscular calcinosis of juvenile dermatomyositis. 17 Regarding the analgesic effect of cimetidine, recent reports indicated an anti-inflammatory mechanism of cimetidine in animal models. Culic et al. showed that low-dose cimetidine had anti-inflammatory activity by reducing nitro-oxidative stress in a rat model of periodontitis, 18 and Aparecida et al. reported that cimetidine reduced the immunoexpression of interleukin-6 and matrix metalloproteinases-1 and -9 in rats with induced periodontal disease. 19
Yokoyama et al. reported that cimetidine was effective for the treatment of chronic calcific periarthritis of the shoulder. 9 In their study, 10 (63%) of 16 patients with chronic calcific periarthritis of the shoulder became painfree after receiving orally administered cimetidine, 200 mg twice a day, which is the same amount as in our study. Calcium deposits disappeared in nine patients (56%), decreased in four patients (25%), and did not change in three patients (19%). Yamamoto et al. reported that famotidine, another H2-receptor antagonist, had an inhibitory effect on osteogenic differentiation of tendon cells in vitro, and oral administration of famotidine also decreased the calcific region in the Achilles tendon in vivo. 20 Famotidine is also reported to have a suppressive effect on progression of ossification of the posterior longitudinal ligament in mice. 21
There are several treatment options for calcific periarthritis such as needle aspiration of the calcium deposits, shock-wave therapy, and surgical excision. Although steroid injections might be effective for acute periarthritis, repetitive injections should be avoided because of the adverse effects such as tendon rupture, postinjection pain, subcutaneous atrophy, and skin pigmentation. Smidt et al. reported that in patients with lateral epicondylitis, corticosteroid injections showed a significant effect at 6 weeks but paradoxically high recurrence rates and poor outcomes at 1 year. 22 Oral administration of cimetidine had few complications and was supposed to be safer than the other treatment options.
There are several limitations in this report. First, we had a small number of cases, and we did not have a control group. Although all the patients had a relatively long history of disease, we could not exclude the possibility that the calcifications diminished spontaneously. Second, the follow-up period is relatively short. Further study is required to elucidate the long-term effect of cimetidine therapy.
In summary, we demonstrated the effectiveness of orally administered cimetidine for chronic calcific periarthritis of the elbow. Although the detailed mechanism of cimetidine’s action on the periarticular calcification remains to be understood, it appears to be a potential therapeutic agent for calcific periarthritis of the elbow.
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.