Commentary on: Middle East Pain Syndrome is A Pollution-Induced New Disease Mimicking Rheumatoid Arthritis

Adel A Elbeialy1*, Abdlnby M Bauomi2, Basma M Elnaggar1, Hala M Elzomor1

1Department of Rheumatology, Al-Azhar faculty of Medicine, Cairo, Egypt

2Department of Radiology, Al-Azhar faculty of Medicine, Cairo, Egypt

Middle East Pain Syndrome (MEPS) is a newly discovered disease, which may be one of the consequences of environmental pollution with heavy metals such as cadmium. It was named so, because all of the patients were from the Middle East, though it might affect people all over the world.

This syndrome comprises a chronic vitamin D3 deficiency or insufficiency, secondary hyperparathyroidism, and fibromyalgia.

Hyperparathyroidism was first linked to arthritis in (1963)1, and then in (1983). Arthritis was found in 11% of hyperparathyroid (HPT) patients, with incidences of erosive arthritis2. Other case studies2-6 had also described HPT presenting as arthritis. Meanwhile, HPT can coexist with inflammatory arthritis such as rheumatoid arthritis on rare occasions7.

In addition to clinical and biochemical characteristics, radiographic characteristics were useful in distinguishing RA and HPT. In contrast to the proximal interphalangeal joints (PIP) of rheumatoid arthritis, HPT can generate bone erosions that are shaggy throughout appearance and scattered in the radiocarpal, radioulnar, metacarpophalangeal, and distal interphalangeal joints8 (Table 1-3).

Table 1:

Demographic data of MEPS study group





Age years

Female Sex

Duration years






18 %








82 %








100 %






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












0 %











Bone resorption and formation are both present in HPT. Bone resorption and sclerosis of many locations in the skeletal system may occur9. Subperiosteal resorption, brown tumors, bone cysts, and sclerosis were found on radiographs, along with osteoclastic resorption of bone, osteoblastic bone production, and fibrous replacement of marrow10 (Table 4).

Table 4:

Different radiological findings in MEPS study group













88 %








Subchondral, subperiosteal, endosteal, intracortical, trabecular, subligamentous, and subtendinous bone resorption are all possible. The early and nearly pathognomonic symptom of HPT is subperiosteal bone resorption, which is characterized by marginal erosions with contiguous bone resorption and sclerosis10 (Figure 1, 2). HPT osteoporosis has a distinct tubal, cigar, or pyramidal look that differs from that of RA or other collagen disorders10 (Figure 1, 2).


Figure 1,2: 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 1: Shows changes in the carpus closely resembling those of rheumatoid arthritis, radiocarpal and scapho-trapezoid joint arthritis.

What distinguishes MEPS from other diseases as hyperparathyroidism, psoriatic, or rheumatoid arthritis, is the presence of tuft spur-like excrescences mimicking that of spade phalanx sign of acromegaly11, but without any other criteria of acromegaly. One literature reported this sign in an unexplained case report12 (Figure 1-4).


Figure 3,4: Zoom of previous Plain X ray hands PA view shows tuft spur-like excrescences mimicking that of (spade phalanx sign) of acromegaly.

Rheumatoid factor (RF) was present in 18% of our patients in low titers, with the absence of anti-cyclic citrullinated peptides antibodies (ACPA). As we know, rheumatoid factor (RF) is not exclusive to RA and can be present in many other conditions such as Epstein–Barr virus or Parvovirus infections, as well as in 5 to 10% of the normal population, especially elderly people13,14. Although our patients were ACPA negative, it is important to note that positivity for ACPA is not diagnostic alone for RA without accomplishment of RA diagnostic criteria. ACPA are produced locally at areas of inflammation, not just in the synovium of RA patients, but also in non-RA conditions. As a result, ACPA positivity may be seen in a subset of patients with diseases other than RA15.

Of course, secondary hyperparathyroidism in our patients is caused by a series of chronic vitamin D3 shortage, and is not caused by renal issues, malignancies, or other reasons. This chronic vitamin D3 shortage was ascribed to possible long-term exposure to the heavy metal cadmium, which is found in some mineral waters, carbonated beverages, fried foods, and tobacco smoke16.

Other possible causes of vitamin D3 shortage in the Middle East despite its plentiful sunshine, are limited sun exposure due to cultural practices, dress styles, limited time spent outdoors, and prolonged breast-feeding without vitamin D supplementation17.

As we know, vitamin D is produced in skin and some other tissues, and metabolized by the liver and kidney into 1,25 dihydroxy vitamin D3 (1,25 (OH)2 D3), the main circulating form of vitamin D. In these pathways, the steroidogenic enzyme cytochrome P450scc, play key roles primarily in the kidney18-21.

Cadmium prefers to accumulate in the kidneys especially in S1 and S2 segments of the proximal tubules, which are responsible for converting 25(OH) D2 to 1,25(OH)2 D3. Cadmium-metallothionein (CdMT) accumulation causes damage in the proximal convoluted tubules, and may contribute to CdMT-induced nephrotoxicity22. Cadmium was also discovered to block the production of the Cytochrome P450scc gene, and therefore its steroidogenic activity23.

Vitamin D3 deficiency as well as HPT have been linked to fibromyalgia syndrome24,25.

Because of the continual removal of calcium from bone, hyperparathyroidism causes bone discomfort and painful joints in people with osteoporosis or osteopenia, as well as chondrocalcinosis and pseudogout. Hemorrhages within the bone can also cause bone discomfort. Calcium pyrophosphate deposition can cause joint discomfort, degenerative arthritis, joint laxity, and muscular weakening26.

The exact incidence of this syndrome is not established yet, because it needs more cohort and multicenter studies. In our practice, more than 40% of previously diagnosed seronegative RA patients, who were not responding to treatment, were found to have MEPS. The diagnosis of this syndrome is not considered without the presence of both tuft spur-like excrescences and arthritis. Otherwise, it could be fibromyalgia or HPT.

This syndrome responds well to a fibromyalgia therapy regimen that includes antidepressants, muscle relaxants, and vitamin D3 supplementation of 5000-10000 iu/day, as well as antioxidants such as selenium, vitamins E, and C. We added sulphasalazine 1 gm/bid or Plaquenil 200 mg/bid to instances with arthritis, to which their inflamed joints responded dramatically. Treatment is continued as long as patient is complaining, with modifications according to the patient status, and it may last for 2 years or more. We advised all patients to abstain from smoking or exposure to smoke; to change food habits to avoid cadmium polluted sources; to change their life styles as much as they can to expose to to more sun light, and to practice gymnastics.


  1. Bywaters EGL, Dixon ASJ, Scott JT. Joint lesions of hyperparathyroidism. Annals of the Rheumatic Diseases. 1963; 22: 171.
  2. Helliwell M. Rheumatic symptoms in primary hyperparathyroidism. Postgrad Med J. 1983; 59: 236-240.
  3. Bywaters EGL, Dixon ASJ, Scott JT. Joint lesions of hyperparathyroidism. Annals of the Rheumatic Diseases. 1963; 22: 171.
  4. Zvaifler NJ, Reefe WE, Black RL. Articular manifestations in primary hyperparathyroidism. Arthritis Rheum. 1962; 5: 237-249.
  5. Lipson RL, Williams LE, Zvaifler NJ, et al. The “connective tissue disorder” of hyperparathyroidism. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 1968; 11: 198-205.
  6. Duraywish AA. Chronic unclassified polyarthritis: A rare presentation of primary hyperparathyroidism. Med J Cairo Univ. 2016; 84: 265-269.
  7. Salari M, Aboutorabi RB, Rezaieyazdi Z. Hypercalcemia and Lytic Bone Lesions Masquerading Inflammatory Arthritis Treated as Rheumatoid Arthritis. Arch Iran Med. 2015; 18: 720-3.
  8. Feng X, McDonald JM. Disorders of bone remodeling. Annu Rev Pathol. 2011; 6: 121-145.
  9. Li N, Li XM, Xu L, et al. Comparison of QCT and DXA: osteoporosis detection rates in postmenopausal women. International Journal of Endocrinology. 2013.
  10. Patel AA, Ramanathan R, Kuban J, et al. Imaging findings and evaluation of metabolic bone disease. Advances in Radiology. 2015.
  11. Killinger Z, Payer J, Lazúrová I, et al. Arthropathy in acromegaly. Rheum Dis Clin North Am. 2010; 36: 713-20.
  12. Freyschmidt J, Brossmann J, Sternberg A, et al. Freyschmidt's "Koehler/Zimmer's Borderlands of Normal and Early Pathological Findings in Skeletal Radiography". 2003.
  13. Falkenburg WJJ. IgG Subclass Specificity Discriminates Restricted IgM Rheumatoid Factor Responses From More Mature Anti–Citrullinated Protein Antibody–Associated or Isotype-Switched IgA Responses. Arthritis & Rheumatology. 2015; 67: 3124–3134.
  14. Edkins A, Cushley W. The Jekyll and Hyde nature of antibodies. Biological Sciences Review. 2012; 25: 2-4.
  15. Vossenaar ER, Smeets TJ, Kraan MC, et al. The presence of citrullinated proteins is not specific for rheumatoid synovial tissue. Arthritis Rheum. 2004; 50: 3485-94.
  16. Elbeialy A, Eldosouky H. AB0984 Cadmium toxicity as a probable cause of smoking induced bone loss. Annals of the Rheumatic Diseases. 2018; 77: 1614.‏
  17. El-Hajj Fuleihan G. Vitamin D Deficiency in the Middle East and Its Health Consequences. In: Holick M. (eds) Vitamin D. Nutrition and Health. Humana Press. 2010.
  18. Bikle D. Vitamin D: Production, Metabolism, and Mechanisms of Action. [Updated 2017 Aug 11]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA):, Inc.; 2000-. Available from:
  19. Slominski AT, Kim TK, Shehabi HZ, et al. In vivo evidence for a novel pathway of vitamin D₃ metabolism initiated by P450scc and modified by CYP27B1. FASEB J. 2012; 26(9): 3901-3915. doi:10.1096/fj.12-208975
  20. Slominski AT, Kim TK, Shehabi HZ, et al. In vivo production of novel vitamin D2 hydroxy-derivatives by human placentas, epidermal keratinocytes, Caco-2 colon cells and the adrenal gland. Mol Cell Endocrinol. 2014; 383(1-2): 181-192. doi:10.1016/j.mce.2013.12.012
  21. Slominski A, Kim TK, Li W, et al. Detection of novel CYP11A1-derived secosteroids in the human epidermis and serum and pig adrenal gland. 2015.
  22. Johri N, Jacquillet G, Unwin R. Heavy metal poisoning: the effects of cadmium on the kidney. Biometals. 2010; 23(5): 783-92. doi: 10.1007/s10534-010-9328-y
  23. Smida AD, Valderrama XP, Agostini MC, et al. Cadmium stimulates transcription of the cytochrome p450 side chain cleavage gene in genetically modified stable porcine granulosa cells. Biol Reprod. 2004; 70(1): 25-31. doi: 10.1095/biolreprod.103.019000
  24. Okumus M, Koybası M, Tuncay F, et al. Fibromyalgia syndrome: is it related to vitamin D deficiency in premenopausal female patients? Pain Manag Nurs. 2013; 14(4): e156-e163. doi: 10.1016/j.pmn.2011.09.006
  25. Bellato E, Marini E, Castoldi F, et al. Fibromyalgia syndrome: etiology, pathogenesis, diagnosis, and treatment. Pain Res Treat. 2012; 2012: 426130. doi:10.1155/2012/426130
  26. Jeremy G. Jones, CHAPTER 32 - Biochemistry of articular disorders, Editor(s): William J. Marshall, Marta Lapsley, Andrew P. Day, Ruth M. Ayling, Clinical Biochemistry: Metabolic and Clinical Aspects (Third Edition), Churchill Livingstone. 2014: 636-645. ISBN 9780702051401.

Article Info

Article Notes

  • Published on: January 21, 2022


  • Middle East Pain Syndrome
  • secondary hyperparathyroidism
  • fibromyalgia
  • hyperparathyroid (HPT) patients


Dr. Adel A Elbeialy,
Department of Rheumatology, Al-Azhar faculty of Medicine, Cairo, Egypt;

Copyright: ©2022 Elbeialy AA. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License.