Middle East Pain Syndrome (MEPS) Vitamin D3 Deciency Induced Hyperparathyroidism And Fibromyalgia Mimicking Rheumatoid Arthritis

Objectives: Musculoskeletal pains are sometimes misdiagnosed in some diseases, like rheumatoid and psoriatic arthritis, erosive OA, etc. Secondary hyperparathyroidism was not considered a differential diagnosis for RA, despite the fact that it can cause arthralgia or arthritis. Also, bromyalgia is a psychosomatic condition marked by widespread pain and tenderness. Methods: This study included 400 patients attended outpatient clinics of Al-Azhar Faculty of medicine in Egypt, and Elaj Specialized Clinics in Saudi Arabia, who were not fullling criteria for RA diagnosis, and not responding to its treatment. Other diseases like psoriatic arthritis and erosive OA were excluded. Criteria for classication of bromyalgia syndrome were applied to all patients. We did lab tests of RF, ACPA, ESR, CRP, LFT, RFT, vitamin D3, PTH, calcium, phosphorus, and SUA. Radiological imaging modalities for diagnosis or exclusion of suspected diseases were applied. Results: All patients were fullling both old and new criteria of bromyalgia syndrome, and not fullling any RA criteria, 18% were seropositive with low RF titers and negative ACPA. All patients had vitamin D3 deciency or insuciency. 75% of patients had abnormally high levels of PTH, and had no parathyroid gland pathology. X-rays showed subperiosteal and subchondral resorption of mainly thumbs, subchondral osteopenia of proximal and middle phalanges, mild subperiosteal resorption along the radial aspect of the middle phalanx and mild tuft erosions, besides changes in the carpus closely resembling those of rheumatoid arthritis, of ulnar styloid resorption, radiocarpal and scapho-trapezoid joint arthritis. Of special interest, the presence of tuft spurs-like excrescences.


Introduction
Secondary hyperparathyroidism (SHPT) is a medical disorder in which the parathyroid glands secrete too much parathyroid hormone (PTH) in reaction to hypocalcemia, resulting in gland hyperplasia. The most prevalent cause of SHPT is chronic renal failure, which is caused by the kidneys' inability to convert enough vitamin D2 to its active form D3, and hence to not adequately excrete phosphate. Insoluble calcium phosphate occurs in the body as a result, removing calcium from circulation. Both of these mechanisms result in hypocalcemia and, as a result, SHPT [1]. Malabsorption (chronic pancreatitis, small bowel disease, malabsorption-dependent bariatric surgery) can also cause SHPT because fat-soluble vitamin D cannot be reabsorbed. As a consequence, hypocalcemia develops, and parathyroid hormone secretion rises in an attempt to raise serum calcium levels. Other factors include a calcium shortage in the diet, a vitamin D de ciency, or steatorrhea. [ 2] Muscle cramps and bone pain are common symptoms of HPT, as are perioral tingling or paresthesia in the ngers or toes, and positive Chvostek and Trousseau signs. Only a few cases of arthritis mimicking rheumatoid arthritis as a presenting characteristic of HPT have been described in the literature. [3] Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects the joints principally which become warm, swollen, and painful. Wrists and hands are the most commonly affected joints, with the same joints being impacted bilaterally. It was previously established that RF is not exclusive to RA and can be present in other disorders such as Epstein-Barr virus or Parvovirus infections, as well as in 5 to 10% of the normal population, especially elderly people. [4,5].
Anti-CCP antibodies are produced locally at areas of in ammation, not just in the synovium of RA patients, but also in non-RA conditions. As a result, anti-CCP positivity may be seen in a subset of patients with diseases other than RA. [6] One of the reasons of SHPT, as we know, is vitamin D3 de ciency, which has been discovered to be frequent in the Middle East, despite the region's abundance of sun rays and hence UV exposure. Heavy metal pollution, such as cadmium and lead, is one of the most likely causes of vitamin D insu ciency in the Middle East. [7,8] The mitochondria of the kidney's proximal convoluted tubule cells produce circulating 1α,25dihydroxyvitamin D3 [1,25(OH)2D3], and parathyroid hormone (PTH) evidently increases 1,25(OH)2D3 production while 1,25(OH)2D3 suppresses PTH production. [9] Cadmium prefers to accumulate in the kidneys. The accumulation of cadmium-metallothionein (CdMT) in the proximal convoluted tubules causes damage as a consequence to renal cadmium deposition.
Vitamin D3 de ciency and hyperparathyroidism have been linked to Fibromyalgia syndrome [11,12].

Patients And Methods
This study included 400 patients attended outpatient clinics of Al-Azhar University Faculty of Medicine Hospitals, Egypt, and Elaj Specialized Clinics, Saudi Arabia, in the period between Nov 2014 to Dec 2019, who were previously diagnosed as RA, but we found them not ful lling any criteria for RA diagnosis, and not responding to treatments including NSAIDs, and DMARDs, ( Table 1).

Inclusion and exclusion criteria:
We got consent from all patients to re-evaluate and re-diagnose them. They were investigated to establish existence of RA, using criteria for classi cation of RA [14,15], with exclusion of other mimicking diseases like psoriatic arthritis, erosive OA, viral arthritis, reactive arthritis, IBD arthritis, Lyme's disease, and palindromic rheumatism. In addition, we applied old and new criteria for classi cation of bromyalgia syndrome to all patients [16,17] to establish the diagnosis of FMS.
We did lab tests of RF, ACPA, ESR, CRP, LFT, RFT, serum 25 cholcalciferol, PTH, total and ionized calcium, phosphorus, and SUA. In addition, all patients did plain X-ray (Toshiba Digital Radiography System, DIGIX U) for hands, knees, and lumbar regions. When recommended, they were exposed to MRI (Philips1.5 tesla), and CT (Multi-Slice spiral CT Aston). High-resolution peripheral quantitative computed tomography (HR-pQCT) imaging allowed for highly reliable assessment of erosion in patients suspected to have RA to exclude them.

Results
All patients scheduled were ful lling both old and new criteria of bromyalgia syndrome, and not ful lling any RA criteria, 82% of them were seronegative and 18% were seropositive with low RF titers and negative ACPA. All patients had vitamin D3 de ciency or insu ciency. 75% of patients had abnormally high levels of PTH (96±12pg/ml), and had no parathyroid gland pathology; hence we called them SHPT group. (Tables 2, 3) X-rays of our patients hands showed subperiosteal and subchondral resorption of mainly thumbs, subchondral osteopenia of proximal and middle phalanges, mild subperiosteal resorption along the radial aspect of the middle phalanx (88%) and mild tuft erosions (12%), besides changes in the carpus closely resembling those of rheumatoid arthritis, of ulnar styloid resorption, radiocarpal and scapho-trapezoid joint arthritis (35%). Of special interest, the presence of tuft spurs-like excrescences (95%) mimicking that of (spade phalanx sign) of acromegaly, but without any other criteria of acromegaly ( Fig.1, 2, 3). Plain X ray of knees showed chondrocalcinosis (20%), intracortical resorption, and osteopenia (Fig 4). Lumbar spine shows mild sclerotic bands of the Superior and inferior end plates mimicking rugger jersey sign (30%), as well as osteopenia and brown tumors (30%).we also detected calcaneal spurs in 45% of patients. (table 4).

Discussion
We found many patients with bilateral wrist and hand arthritis had a combination of vitamin D3 de ciency, increased serum parathyroid hormone, and bromyalgia. They were misdiagnosed as having either seronegative or seropositive rheumatoid arthritis, resulting in treatment failure and long-term pain. We revaluated them as having a new syndrome, of vitaminD3 de ciency, FMS, and SHPT, we named it Middle East Pain Syndrom (MEPS), since all patients we discovered were from Middle East.
A study by Helliwell showed arthritis in 11% of HPT patients, including two cases of erosive arthritis [18]. Also, HPT presenting as arthritis had been described in other case reports [18][19][20][21][22]. Meanwhile, HPT itself, can occasionally co-exist with in ammatory arthritis like rheumatoid arthritis [23]. In addition to clinical and biochemical features, radiographical features were helpful to differentiate both. HPT does not cause only osteoporosis and pathological fractures, it can cause also bone erosions, which are shaggy in appearance and distributed in the radiocarpal, radioulnar, metacarpophalangeal and distal interphalangeal joints, in contrast to that which predominate PIP joints of rheumatoid arthritis [24].
HPT is characterized by both bone resorption and formation. Plain radiography results may include resorption and sclerosis of multiple places in the skeletal system as a result [25]. Bone ndings were characterized by the osteoclastic resorption of bone, osteoblastic bone formation, and brous replacement of marrow, with radiographic ndings of subperiosteal resorption, brown tumors, bone cysts, and sclerosis. [26] The disease may progress with further destruction that results in a ground-glass appearance in bone trabeculae [26]. Bone resorption may be interpreted as subperiosteal, intracortical, trabecular, endosteal, subchondral, subligamentous, or subtendinous. Subperiosteal bone resorption is an early and virtually pathognomonic sign of HPT, which is marked by marginal erosions with adjacent resorption of bone and sclerosis. Although subperiosteal bone resorption can affect many sites, the most common site in HPT is the middle phalanges of the index and middle ngers, primarily on the radial aspect [26]. HPT osteoporosis attains a characteristic tubal, cigar or pyramidal like appearance, other than that found in RA or other collagen diseases. Of special interest, the presence of tuft spur-like excrescences mimicking that of spade phalanx sign of acromegaly [27], but without any other criteria of acromegaly. One literature reported this sign in an unexplained case report, [28].
Of course, the secondary hyperparathyroidism found in our patients is a sequence of chronic vitamin D3 de ciency or insu ciency, and not associated with renal problems, nor malignancies, or other precipitating factors. We attributed this chronic vitamin D3 de ciency or insu ciency to probable long term exposure to pollutants, as the heavy metals cadmium and lead, present in some mineral waters, zzy waters, fried snacks, and tobacco smoke. [7,8,29].
Vitamin D is produced in the skin from 7-dehydrocholesterol by UV irradiation. The liver and other tissues metabolize vitamin D, whether from the skin or oral ingestion, to 25OHD, the principal circulating form of vitamin D. 25OHD is then further metabolized to 1,25(OH)2D principally in the kidney, by the enzyme CYP27B1. 1,25(OH)2D is the principal hormonal form of vitamin D, responsible for most of its biologic actions. [30] Cadmium preferentially selects to settle in kidneys. Renal cadmium deposition induces injury resulted from accumulation of cadmium-metallothionein (CdMT) in the proximal convoluted tubules. CdMTinduced nephrotoxicity might be due, at least in part, to its preferential uptake of CdMT into the S1 and S2 segments of the proximal tubules, which is responsible for converting 25(OH)D3 to 1,25(OH)2D3. [31].
Hyperparathyroidism is a cause of bone pain and aching joints due to osteoporosis or osteopenia because of the continued removal of calcium from bone as well as chondrocalcinosis and pseudogout. Bone pain may also be caused by hemorrhages within the bone. Joint pains, degenerative arthritis, joint laxity and muscle weakness can result from calcium pyrophosphate deposition. [34]. This chronic suffering from vitamin D3 de ciency or insu ciency induces SHPT, which in turn induces musculoskeletal perturbance in the form of muscle and tendon pain and weakness, bone and joint pains.
This syndrome responds well to treatment of bromyalgia regimen with SSRI, muscle relaxants, and vitamin D3 supplementation 5000-10000 iu/day, antioxidants including selenium, vitamins E and C. In cases with arthritis we add sulphasalazine 1 gm/bid or Plaquenil 200 mg/bid to which their in amed joints respond signi cantly.

Conclusion
Middl East Pain Syndrome is a new disease, which must be given more attention for diagnosis, and more extensive studies for its pathogenesis, prevention. and cure. Cadmium pollution must be considered as one of the new millennium big challenges that should be treated e ciently, to prevent many economically affecting health hazards.

Declarations
All authors con rm that there are no any potential con icts of interest of each of them. We con rm hereby that the manuscript has not been submitted or is not simultaneously being submitted elsewhere, is not at the time of submission under consideration by another journal or other publication, and that no portion of the data has been or will be published elsewhere while the manuscript is under review by the journal, unless rejected or withdrawn by the author. Also we con rm that no portion of the data has been or will be published elsewhere while the manuscript is under review by the journal.
We con rm also that there is not any nancial support or other bene ts from commercial sources for the work reported on in the manuscript, or any other nancial interests that any of the authors may have, which could create a potential con ict of interest or the appearance of a con ict of interest with regard to the work.     Mild subperiosteal bone resorption affecting radial aspects of the proximal and middle phalanges of the 2nd and 3rd ngers. No subligamentous resorption. Terminal tuft erosion (acro-osteolysis), changes in the carpus closely resembling those of rheumatoid arthritis, radiocarpal and scapho-trapezoid joint arthritis. as well as spur-like excrescences.

Figure 2
Subperiosteal bone resorption affecting radial aspects of the proximal and middle phalanges of the 2nd and 3rd ngers. Terminal tuft cysts (acro-osteolysis), as well as spur-like excrescences.