RETRACTED ARTICLE: Middle east pain syndrome is a pollution-induced new disease mimicking rheumatoid arthritis

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, fibromyalgia is a psychosomatic condition marked by widespread pain and tenderness. This study included 400 patients attended certain outpatient clinics of Rheumatology in Egypt and Saudi Arabia, who were not fulfilling criteria for RA diagnosis. Criteria for classification of fibromyalgia syndrome were applied to all patients. We did lab tests and radiological imaging modalities for diagnosis or exclusion of suspected diseases were applied. All patients were fulfilling both old and new criteria of fibromyalgia syndrome, and not fulfilling any RA criteria, and had vitamin D3 deficiency or insufficiency. 75% of patients had abnormally high levels of PTH, without parathyroid gland pathology. Radiology 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 spur-like excrescences.

Inclusion and exclusion criteria.We got informed consent from all patients to re-evaluate and re-diagnose them.All methods were carried out in accordance with relevant guidelines and regulations.Patients were investigated to establish existence of RA, using criteria for classification 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 classification of fibromyalgia 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 (Philips1.5T), 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.
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Results
All patients scheduled were fulfilling both old and new criteria of fibromyalgia syndrome, and not fulfilling any RA criteria, 82% of them were seronegative and 18% were seropositive with low RF titers and negative ACPA.All patients had vitamin D3 deficiency or insufficiency.75% of patients had abnormally high levels of PTH (96 ± 12 pg/ml), and had no parathyroid gland pathology (Tables 2, 3).

R E T R A C T E D A R T I C L E
the Superior and inferior end plates mimicking rugger jersey sign (30%), as well as osteopenia and brown tumors (30%).wealso 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 deficiency, fibromyalgia, and sometimes increased serum parathyroid hormone.They were misdiagnosed as having either seronegative or seropositive rheumatoid arthritis, resulting in failure of treatment and long-term pain.We revaluated them as having a new syndrome, of vitaminD3 deficiency, FMS, and SHPT; we named it Middle East Pain Syndrom (MEPS), since all patients 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 inflammatory 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 findings were characterized by the osteoclastic resorption of bone, osteoblastic bone formation, and fibrous replacement of marrow, with radiographic findings 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    www.nature.com/scientificreports/ the index and middle fingers, 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 deficiency or insufficiency, and not associated with renal problems, nor malignancies, or other precipitating factors.We attributed this chronic vitamin D3 deficiency or insufficiency to probable long term exposure to pollutants, as the heavy metals cadmium and lead, present in some mineral waters, fizzy waters, fried snacks, and tobacco smoke 7,8,29 .
Cadmium preferentially selects to settle in kidneys.Renal cadmium deposition induces injury resulted from accumulation of cadmium-metallothionein (CdMT) in the proximal convoluted tubules.CdMT-induced 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 34 .In addition, cadmium was found to inhibit expression of the p450scc (CYP11A1) gene and consequently its steroidogenic function 35 .
Vitamin D3 deficiency and HPT are established to be associated with Fibromyalgia syndrome 36,37 .Hyperparathyroidism is known to be associated with multiple articular manifestations including gout, pseudogout, juxtaarticular erosions, tenosynovitis, periarthritis, and pericapsular calcification 12 .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 38 .This chronic suffering from vitamin D3 deficiency or insufficiency 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 fibromyalgia regimen with SSRI, muscle relaxants, and vitamin D3 supplementation 5000-10,000 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 inflamed joints respond significantly.

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 efficiently, to prevent many economically affecting health hazards.

Figure 1 .Figure 2 .
Figure 1.Plain X ray hand PA view shows mild subperiosteal bone resorption affecting radial aspects of the proximal and middle phalanges of the 2nd and 3rd fingers, terminal tuft erosions (acro-osteolysis), as well as spur-like excrescences.Figure shows changes in the carpus closely resembling those of rheumatoid arthritis, radiocarpal and scapho-trapezoid joint arthritis.

Figure 3 .
Figure 3. Zoom of previous Plain X ray hands PA view shows tuft spur-like excrescences mimicking that of (spade phalanx sign) of acromegaly.

Figure 4 .
Figure 4. Zoom of previous Plain X ray hands PA view shows tuft spur-like excrescences mimicking that of (spade phalanx sign) of acromegaly.

Table 1 .
Demographic data of MEPS study group.

Table 2 .
Laboratory chemistry and PTH results of MEPS study group.ESR erythrocyte sedimentation rate, SUA serum uric acid, Ca total calcium, Ca++ ionized calcium, D3 vitamin D3, PTH parathyroid hormone, P serum phosphorus.

Table 3 .
Different Criteria Domains in MEPS study group.RN rheumatoid nodules, Dur duration, CCP anti-CCP, RF rheumatoid factor, TTP tender trigger points, SSS symptom severity score, WPI widespread pain index.